@article {pmid42877349,
year = {2026},
author = {Yuan, X and Tang, Q and Wang, T},
title = {Screening of herbs for vascular dementia: Through the combination of reverse network pharmacology and traditional Chinese medicine enrichment analysis.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261466619},
pmid = {42877349},
issn = {2542-4823},
abstract = {BACKGROUND: Vascular dementia (VaD) represents the second most prevalent form of cognitive impairment following Alzheimer's disease. Its pathological mechanisms encompass a complex interplay of cerebral ischemia, inflammatory responses, oxidative stress, and neuronal apoptosis. Current clinical interventions predominantly target cerebral circulation enhancement and neuroprotection; however, these approaches exhibit limitations in efficacy, single-target specificity, and significant adverse effects. Traditional Chinese medicine (TCM) offers a novel therapeutic paradigm for complex diseases owing to its multi-target synergistic effects, low toxicity profile, and integrated preventive and therapeutic benefits.

OBJECTIVE: This study aims to identify the potentially effective active components in TCM targeting VaD, and to elucidate the multi-target regulatory mechanisms.

METHODS: This study employed a "disease-gene-drug" reverse screening model, integrating bioinformatics and network pharmacology, to systematically identify potential TCM candidates for VaD treatment and elucidate their multi-target regulatory mechanisms.

RESULTS: A total of eight TCM agents with potential VaD therapeutic efficacy (including Niuxi, Pueraria lobata, and Citrus aurantium) were identified, alongside nine active compounds and nine therapeutic targets. Notably, Gehua and Zhike were reported for the first time to exhibit potential VaD therapeutic effects. Furthermore, molecular docking technology was utilized to investigate the binding affinity and interaction modes of these nine active compounds with key targets.

CONCLUSIONS: To our knowledge, this study is among the first to apply reverse network pharmacology combined with TCM enrichment specifically to VaD.},
}

@article {pmid42877369,
year = {2026},
author = {Shrestha, N and Chiang, C and Wei, YJ},
title = {Central nervous system-active medication polypharmacy and risk for nursing home admission among adults with early-onset dementia: A retrospective cohort study.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261472831},
pmid = {42877369},
issn = {2542-4823},
abstract = {BACKGROUND: While central nervous system (CNS)-active medication polypharmacy is prevalent among adults with early-onset dementia (EOD), its impact on nursing home (NH) admission is unclear.

OBJECTIVE: To examine whether CNS-active medication polypharmacy is associated with risk for NH admission among patients with EOD.

METHODS: A retrospective cohort study using 2012-2021 MarketScan Databases was conducted with adults aged 30 to 64 years diagnosed with Alzheimer's disease and related dementias (ADRD). CNS-active medication polypharmacy was assessed during a fixed 6-month period after an indexed ADRD diagnosis and defined as concurrent use of ≥3 CNS-active medications on the American Geriatrics Society Beers Criteria list that overlapped for ≥30 consecutive days. Cox hazards models were used to estimate the hazard ratio (HR) of NH admission between patients with versus without CNS-active medication polypharmacy, with adjustment for baseline covariates via inverse probability of treatment weighting.

RESULTS: Of the 18,029 patients with EOD identified, those with CNS-active medication polypharmacy (versus those without) had an increased risk of NH admission (HR, 1.34 [95% CI, 1.16-1.56]). The risk was pronounced in patients aged >50 years, male patients, patients with a diagnosis of Alzheimer's disease or senile dementia, and patients having baseline use of anti-dementia medications.

CONCLUSIONS: In this commercially insured population of adults with EOD, receipt of CNS-active medication polypharmacy was associated with risk for NH admission. The finding, however, should be interpreted with caution, as it may reflect differences in the underlying disease severity and clinical indications treated by the studied CNS-active medications.},
}

@article {pmid42877383,
year = {2026},
author = {Ferrer, A and Moon, J},
title = {Lecanemab real-world treatment outcomes from cohort study in early Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261470042},
pmid = {42877383},
issn = {2542-4823},
abstract = {Lecanemab has demonstrated amyloid reduction and slowed clinical decline in early Alzheimer's disease trials. Herein, we report retrospective case series results on lecanemab treatment in our clinic. Overall, 61 individuals were included. For the 33 patients with Kokmen Mental Status Exam baseline and post-baseline scores, 67% had either improved or stable scores. Nine incident amyloid-related imaging abnormalities were observed with all but one patient continuing treatment. Six patients were safely transitioned from aducanumab to lecanemab treatment upon market withdrawal of aducanumab. In a real-world clinical practice setting, the lecanemab effectiveness and safety profile were similar to that observed in clinical studies.},
}

@article {pmid42877391,
year = {2026},
author = {Granadillo, E and Peterson, A and Bloyer, E and Hancock, LM and Shah-Basak, P and Kraegel, P and Schold, S and Okonkwo, O and Nair, VA and Prabhakaran, V and Ikonomidou, C},
title = {Multifield extended high-definition transcranial direct current stimulation in mild cognitive impairment: A proof-of-concept study on cognition and brain network connectivity.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261449802},
pmid = {42877391},
issn = {2542-4823},
abstract = {BACKGROUND: Treatment of mild cognitive impairment (MCI) could delay the progression of cognitive decline. Noninvasive neuromodulation might restore brain plasticity and lead to clinically meaningful cognitive improvements.

OBJECTIVE: To investigate feasibility and tolerability of a multi-field (four regions) extended (80-min-long) intervention using high-definition transcranial direct current stimulation (HD-tDCS) combined with computerized cognitive training (CCT) in participants with MCI and to explore its effects on cognition and brain functional connectivity.

METHODS: Double-blinded, randomized proof-of-concept trial of daily sham HD-tDCS + CCT (n = 4) or anodal HD-tDCS + CCT (n = 4) for 15 sessions over 3 months. Four cortical regions were targeted using neuronavigation, including putative frontal coordinates of cognitive reserve and lateral parietal coordinates hypothesized to have robust hippocampal connectivity. Neurocognitive outcomes were assessed at 3 and 6 months and resting-state functional connectivity changes were evaluated at 3 months. Statistical analysis included independent sample t-tests, Wilcoxon rank-sum tests, and Bonferroni correction for multiple comparisons.

RESULTS: Eleven subjects were eligible and interviewed, and 8 consented (73% consent rate). All 8 completed the trial with only minor adverse events (100% completion rate). Blinding was successful. A large but non-significant increase in Alzheimer's Disease Cooperative Study-Preclinical Alzheimer's Cognitive Composite scores at 6 months was observed in the anodal group (59.8%) compared with sham (24.5%). Significant declines were seen in left parietal cortex-left caudal hippocampus connectivity (p = 0.004) and right intraparietal sulcus-right frontal eye fields connectivity (p = 0.039) in the anodal group.

CONCLUSIONS: The intervention was feasible and well tolerated. Findings suggest possible normalization of aberrant or compensatory hyperconnectivity in MCI. Larger studies are needed.Clinical Trial Number: NCT04246164.},
}

@article {pmid42877397,
year = {2026},
author = {Yano, K and Nagata, T and Nakajima, S and Kito, S and Shinagawa, S},
title = {The trajectory of delusions in patients with Alzheimer's disease receiving pharmacological treatment: A re-analysis of data from the CATIE-AD trial.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261494480},
pmid = {42877397},
issn = {2542-4823},
abstract = {BACKGROUND: Previous studies have reported decreases in the proportion of patients with delusions and severity of delusions during long-term follow-up in Alzheimer's disease (AD).

OBJECTIVE: The aim of the present study was to explore clinical predictors of the disappearance of delusions in AD patients enrolled in the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) trial who received pharmacological treatment.

METHODS: We re-analyzed the data of 421 clinic-based patients enrolled in the CATIE-AD trial to examine the association between the disappearance of delusions and relevant factors selected by reference to previous studies at week 12, 24, and 36 of treatment. Generalized Estimating Equations were used to analyze the impact of the assigned medication (mainly atypical antipsychotics), treatment duration, and their interaction on the disappearance of delusions over time.

RESULTS: The proportion of patients with delusions (PWD) gradually decreased to approximately 50% over the 36-week treatment period; however, no significant differences in the baseline variables were identified between the PWD and patients without delusions (POD) at any of the follow-up time-points (weeks 12, 24, or 36). Furthermore, the treatment duration was found to contribute significantly to the disappearance of delusions over time (conversion from PWD at baseline to POD at subsequent follow-up visits), independent of active drug use.

CONCLUSIONS: Disappearance of delusions in AD patients was associated with the interval from the baseline, regardless of the use of active drugs. Insights into the natural course of delusions could guide clinicians toward selecting alternative treatment strategies for patients with AD.},
}

@article {pmid42877407,
year = {2026},
author = {Horowitz, R},
title = {Improving biomarkers of inflammation including phosphorylated tau in a patient with chronic Lyme disease/post-treatment Lyme disease syndrome using dapsone combination therapy: A case study and literature review.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261445434},
pmid = {42877407},
issn = {2542-4823},
abstract = {BACKGROUND: Borrelia burgdorferi, the agent of Lyme disease, has been found to co-localize in Alzheimer's disease autopsy brain tissues with biofilm, amyloid, and phosphorylated tau.

OBJECTIVE: To determine whether dapsone combination therapy (DCT), a biofilm/persister antibiotic regimen with good central nervous system penetration can improve p-tau and peripheral inflammatory markers in a patient with chronic Lyme disease (CLD)/post-treatment Lyme disease syndrome (PTLDs).

METHODS: A 67-year-old female with CLD/PTLDs, and Ehrlichia, Babesia, Bartonella, and Coxiella burnetii had a 15-year history of joint pain with inflammation and mild cognitive impairment despite prior treatment with doxycycline. She was checked for changes in peripheral inflammation, i.e., rheumatoid factors (RFs) and changes in serum p-tau181, p-tau 217, and amyloid-β (Aβ) 42:40 ratios before and after treatment with DCT.

RESULTS: Elevated RFs at 20 IU/mL decreased into normal range three months post treatment accompanied by a decrease in pain with improved flexibility. An initially elevated serum p-tau 217 level in the blood at 0.33 pg/mL (normal range <0.15 pg/mL) prior to using DCT normalized, decreasing to 0.12 pg/mL three months post therapy, while p-tau 181 levels remained within normal limits. Aβ ratios simultaneously improved post DCT increasing from 0.185 pg/mL to 0.216 (normal range >0.170) accompanied by subjective improvements in concentration and recall.

CONCLUSIONS: This is the first case study proving that a short term, biofilm/persister drug regimen, i.e., DCT, can potentially improve peripheral autoantibodies (RFs) and pathological triggers of neuroinflammation (p-tau, Aβ) in a patient with CLD/PTLDs.},
}

@article {pmid42877439,
year = {2026},
author = {Su, CY and Wong, YS and Lee, C and Sung, SF and Wu, CS and Su, YH and Lin, MH and Ong, CT},
title = {Higher thyroid-stimulating hormone level may delay dementia progression in patients without thyroid dysfunction.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261494184},
pmid = {42877439},
issn = {2542-4823},
abstract = {BACKGROUND: Although thyroid dysfunction causes reversible cognitive impairment, the role of thyroid-stimulating hormone (TSH) variation within the normal range in dementia progression remains unclear.

OBJECTIVE: To evaluate the association between baseline euthyroid TSH levels and cognitive decline rate in dementia patients.

METHODS: We conducted a retrospective cohort study using Taiwan's Ditmanson Research Database (2015-2022). Dementia patients with normal thyroid function who initiated anti-dementia medication were included; those with overt thyroid disease, malignancy, or CNS infections were excluded. Baseline TSH (within 180 days prior to treatment) was stratified by the cohort median (1.392 μIU/mL) into Low and High TSH groups. Longitudinal cognitive outcomes were tracked via repeated Mini-Mental State Examination (MMSE) scores over 3 years. Generalized estimating equation (GEE) models evaluated the TSH-cognitive decline association, adjusting for age, sex, baseline MMSE, medication class, and vascular comorbidities.

RESULTS: A total of 402 patients (955 MMSE observations) were analyzed. Baseline characteristics were comparable between groups. In adjusted analyses, the Low TSH group declined by 1.44 MMSE points per year (95% CI: -1.90 to -0.97; p < 0.001). A significant time-by-TSH group interaction (beta = 0.76, 95% CI: 0.17 to 1.34; p = 0.011) indicated a slower annual decline in the High TSH group (-0.68 points/year).

CONCLUSIONS: Among euthyroid dementia patients, higher baseline TSH levels within the reference range were associated with significantly slower cognitive decline. These findings suggest physiological TSH variations may influence neurodegenerative progression, warranting further prospective research to clarify causality.},
}

@article {pmid42877443,
year = {2026},
author = {Lusk, JB and Fitch, KV and Johnson, KG and Liu, A and Lund, JL and Thomas, LE and McDevitt, R and Zhao, A and Whitson, HE and O'Brien, R and Aymes, S and Hammill, BG and Mac Grory, B and Li, F and O'Brien, EC},
title = {Uptake and safety profile of anti-amyloid immunotherapies in routine clinical practice.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261483526},
pmid = {42877443},
issn = {2542-4823},
abstract = {BACKGROUND: Anti-amyloid immunotherapies are approved by the United States Food and Drug Administration for the treatment of Alzheimer's disease; however, the adoption and safety profile of these medications in routine clinical practice have not been described.

OBJECTIVE: To describe the adoption and safety profile of anti-amyloid immunotherapies in routine clinical practice.

METHODS: This was a retrospective observational cohort study using target trial emulation methods. The data source was nationwide electronic health record data from Epic Cosmos. The primary exposure was the first prescription of anti-amyloid immunotherapy versus the active comparator of oral dementia therapy (acetylcholinesterase inhibitor (AChEI) or memantine, selected to minimize bias by baseline health status and disease severity). The primary end point was time to first nontraumatic intracranial hemorrhage (ICH). Propensity score overlap weighting was used to balance baseline demographic and clinical characteristics across treatment groups.

RESULTS: Between July 1, 2023 and January 1, 2025, 2616 patients (median age 74.8 years [IQR 69.8-78.8]; 53.9% female) were prescribed anti-amyloid immunotherapy (with or without AChEI/memantine), and 1,065,192 patients (median age 79.98 [IQR 73.6-85.6], 57.9% female) were prescribed AChEI/memantine alone. In total, 401 patients prescribed anti-amyloid immunotherapy and 274,470 patients prescribed AChEI/memantine were assessed for safety endpoints. Compared with AChEI/memantine, the analysis did not detect a statistically significant association between prescription of anti-amyloid immunotherapy and ICH (owHR 0.73 [95% CI 0.10-5.12]).

CONCLUSIONS: The study did not detect a statistically significant association between prescription of anti-amyloid immunotherapy and ICH. The small treated cohort and low event count yielded imprecise estimates; these findings do not confirm safety and cannot exclude a clinically important increase in risk.},
}

@article {pmid42877463,
year = {2026},
author = {Takahashi, Y and Shiraishi, N and Tsukahara, A and Matsuda, Y and Nishina, T and Yoshikawa, H and Uzu, T and Mori, E},
title = {Symptomatic lobar intracerebral hemorrhage during extended lecanemab treatment: A case report.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261487915},
pmid = {42877463},
issn = {2542-4823},
abstract = {Lecanemab is an anti-amyloid-β protofibril antibody that slows cognitive decline in early Alzheimer's disease. Although amyloid-related imaging abnormalities (ARIA) occur predominantly early in treatment, reports of hemorrhagic events during extended treatment beyond 18 months remain limited. A 77-year-old woman completed a standard 1.5-year lecanemab regimen without ARIA on surveillance MRIs. The day after her 42nd infusion, she acutely developed confusion and incomprehensible speech. MRI revealed a 2.5-cm left parietal subcortical hemorrhage. This case highlights that symptomatic lobar hemorrhage may occur even during extended lecanemab therapy, underscoring the importance of continued safety monitoring during extended treatment.},
}

@article {pmid42877495,
year = {2026},
author = {Cabrera-Martín, MN and Aguiar-Fernández, P and Camacho-Martí, V and Guillén-Valderrama, EF and Jiménez-Bonilla, JF and Lojo-Ramírez, JA and López-Mora, DA and Matías-Guiu, JA and Paredes-Rodríguez, P and Perissinotti, A and Arbizu, J},
title = {Current use and perspectives of PET imaging in Alzheimer's disease: A Spanish national survey.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261437129},
pmid = {42877495},
issn = {2542-4823},
abstract = {BACKGROUND: Novel therapies for Alzheimer's disease are expected to increase the demand for biomarkers. PET will likely play a central role in patient selection and treatment monitoring, requiring adequate infrastructure and trained professionals.

OBJECTIVE: To assess the current status of Nuclear Medicine departments in Spain regarding organization, expertise, and available infrastructure.

METHODS: We conducted a nationwide survey among Nuclear Medicine departments in Spain.

RESULTS: Respondents averaged 19.8 years of professional experience; 62.0% had specific neuroimaging training and 76.0% reported high confidence in amyloid PET interpretation. Hospitals were mainly public (70.6%) and widely distributed geographically, and 73.0% reported having cognitive impairment units. Following the INVEAT plan, Spain currently has 147 PET scanners, although capacity varies: most centers operate one scanner and five reported having none. Amyloid PET is available in 77.0% of departments, with annual volumes ranging from fewer than 10 to more than 100 studies; 15.0% cannot perform amyloid PET due to regional limitations. Quantification tools are available in 41.3% of centers, although only 15.5% include quantitative metrics in reports, while 66.7% support the use of centiloid standardization. Nearly all respondents anticipate increased indications for amyloid PET (screening 83.7%; monitoring 68.5%) and support multidisciplinary collaboration (89.1% favor Neuroimaging Committees). About half report workforce needs, mainly nuclear medicine physicians (46.2%). Research activity in Alzheimer's disease is expected to increase (95.6%).

CONCLUSIONS: Most departments recognize the key role of amyloid PET for anti-amyloid therapy implementation and anticipate increased demand, highlighting the need to expand availability, implement quantification tools, and strengthen multidisciplinary collaboration.},
}

@article {pmid42877510,
year = {2026},
author = {Abdelkader, MS and Atalah, HN and Mamdouh, A and Ghazal, R and Bakr, M and Salama, M},
title = {Retinal tau imaging and histopathology as emerging Alzheimer's disease biomarkers: A systematic review.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823251391710},
pmid = {42877510},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposition and tau protein aggregation. The retina, as an extension of the central nervous system, has emerged as a promising site for detecting biomarkers of AD.

OBJECTIVE: This systematic review synthesizes the current evidence on retinal tau protein as a diagnostic tool for AD and related tauopathies.

METHODS: This systematic review adhered to PRISMA guidelines, analyzing studies on retinal tau biomarkers, structural changes, and diagnostic imaging techniques. The included studies encompassed molecular investigations, experimental models, and clinical imaging approaches.

RESULTS: Retinal phosphorylated tau (p-tau) and related isoforms were consistently identified as correlating with systemic AD pathology, including Braak staging. Experimental and clinical studies revealed early retinal changes, such as ganglion cell degeneration and blood-retina barrier breakdown, that preceded cognitive decline. Diagnostic advancements, including curcumin fluorescence imaging, ferritin nanocages, and hyperspectral imaging, demonstrated enhanced precision and feasibility for detecting retinal tau and Aβ in vivo and postmortem. These findings suggest that retinal tau serves as a robust biomarker for AD.

CONCLUSIONS: Retinal tau pathology represents a powerful diagnostic tool, providing non-invasive access to early AD pathology. By integrating molecular insights with advanced imaging modalities, retinal biomarkers could enable earlier diagnosis, therapeutic monitoring, and personalized treatment strategies. Future research should focus on longitudinal validation of retinal biomarkers across diverse populations.},
}

@article {pmid42877578,
year = {2026},
author = {Wang, R and Yang, Q and Cao, Z and Zhou, J and Tian, B and Wang, X and Zhang, X and Xiang, Q and Chen, G},
title = {From scavenger to victim: mechanism and treatment of microglial ferroptosis in white matter injury disease.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1859981},
pmid = {42877578},
issn = {1664-3224},
mesh = {*Ferroptosis ; Humans ; *Microglia/metabolism/pathology/immunology ; Animals ; *White Matter/pathology/metabolism/injuries/immunology ; Iron/metabolism ; *Leukoencephalopathies/metabolism/pathology ; Lipid Peroxidation ; Myelin Sheath/metabolism ; },
abstract = {Failure of myelin repair is a shared pathological feature of white matter injury (WMI)-associated diseases, including Alzheimer's disease (AD), vascular dementia (VaD), and multiple sclerosis (MS), but the underlying mechanisms remain incompletely understood. Microglia, the resident innate immune cells of the central nervous system (CNS), contribute to white matter homeostasis by clearing myelin debris and supporting remyelination. Within the iron- and lipid-rich white matter microenvironment, sustained uptake of myelin and oligodendroglial debris may impose phagocytic and metabolic stress on microglia, thereby increasing their susceptibility to ferroptosis, an iron-dependent form of regulated cell death driven by membrane phospholipid peroxidation. This susceptibility is regulated by interconnected mechanisms involving ferritinophagy-associated iron dysregulation, ACSL4/NOX2/15-LOX-related lipid peroxidation, and impaired endogenous ferroptosis-defense systems. Microglial responses are also heterogeneous: disease-associated, demyelination-associated, white matter-associated, lipid-droplet-accumulating, and degenerative microglial programs represent partially overlapping and context-dependent states rather than a proven linear trajectory. In susceptible microglial subsets, ferroptosis or ferroptosis-associated dysfunction may impair debris clearance and trophic support while promoting oxidized lipid accumulation and inflammatory signaling, thereby limiting remyelination. This review summarizes current evidence on the molecular mechanisms, multicellular interactions, microglial states, disease contexts, and therapeutic strategies associated with microglial ferroptosis in WMI. We further propose a functional therapeutic-window framework based on phagocytic competence, iron-lipid handling capacity, antioxidant reserve, and evidence of ferroptotic injury, and discuss major challenges in clinical translation. Overall, current evidence supports microglial ferroptosis as a context-dependent contributor to myelin repair failure rather than a universal determinant.},
}

*Ferroptosis
Humans
*Microglia/metabolism/pathology/immunology
Animals
*White Matter/pathology/metabolism/injuries/immunology
Iron/metabolism
*Leukoencephalopathies/metabolism/pathology
Lipid Peroxidation
Myelin Sheath/metabolism

@article {pmid42877708,
year = {2026},
author = {Li, S and Yu, Y and Cunanan, V and Masaki, K and Ross, GW},
title = {Lifestyle, APOE ε4, amyloid burden, and race/ethnicity differences in cognition, mood, and anxiety among cognitively unimpaired older adults.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70494},
pmid = {42877708},
issn = {2352-8729},
abstract = {INTRODUCTION: We assessed whether lifestyle, race/ethnicity, and apolipoprotein E gene (APOE) ε4 were associated with cognition or mood/anxiety.

METHODS: This secondary cohort analysis used data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) cohort. Cognitively unimpaired adults aged 65 to 85 years (n = 1705) reported baseline lifestyle behaviors (summed as healthy lifestyle index [HLI]). APOE ε4 carrier status and amyloid positron emission tomography were assessed at baseline, while cognitive, anxiety, and depressive outcomes were assessed longitudinally. Associations were tested using mixed-effects models.

RESULTS: Among Non-Hispanic White participants, higher HLI was associated with fewer depressive symptoms, sufficient sleep was associated with smaller ε4-related increases in anxiety, and excessive alcohol use amplified ε4-related cognitive decline. Among participants from other racial/ethnic groups, walking and higher HLI were associated with more favorable anxiety/depression trajectories.

DISCUSSION: Adequate sleep, limited alcohol, walking, and no smoking may support emotional and cognitive health.},
}

@article {pmid42341744,
year = {2026},
author = {Marth, L and Lund, A and Höglinger, G and Levin, J},
title = {[Dementia with Lewy bodies].},
journal = {Fortschritte der Neurologie-Psychiatrie},
volume = {94},
number = {9},
pages = {340-350},
pmid = {42341744},
issn = {1439-3522},
support = {EXC 2145 SyNergy ID 390857198//Deutsche Forschungsgemeinschaft/ ; },
mesh = {Humans ; *Lewy Body Disease/diagnosis/therapy/psychology/pathology/epidemiology ; alpha-Synuclein/metabolism ; Biomarkers ; Lewy Bodies/pathology ; },
abstract = {Dementia with Lewy bodies (DLB) is the second most common neurodegenerative type of dementia after Alzheimer’s disease and belongs to the atypical parkinsonian syndromes. It is characterized by cognitive fluctuations, visual hallucinations, REM sleep behavior disorder, and parkinsonism. Typically, cognitive impairment appears before or within one year after the onset of motor symptoms (“one-year rule”). Neuropathologically, DLB is an α-synucleinopathy with neuronal Lewy bodies, often accompanied by copathologies. Diagnosis is based on clinical McKeith criteria and often supported by imaging biomarkers. Treatment is mainly symptomatic. Disease-modifying therapies are not yet available but are being investigated in clinical trials. The development of biologically defined diagnostic criteria and molecular biomarkers is crucial for future therapeutic studies.},
}

Humans
*Lewy Body Disease/diagnosis/therapy/psychology/pathology/epidemiology
alpha-Synuclein/metabolism
Biomarkers
Lewy Bodies/pathology

@article {pmid42870221,
year = {2026},
author = {Lee, GY and Han, SN},
title = {The Receptor for Advanced Glycation End Products: Regulation and Implications in Metabolic Diseases.},
journal = {IUBMB life},
volume = {78},
number = {10},
pages = {e70137},
doi = {10.1002/iub.70137},
pmid = {42870221},
issn = {1521-6551},
support = {NRF-RS-2024-00353119//National Research Foundation (NRF) of Korea/ ; },
mesh = {Humans ; *Receptor for Advanced Glycation End Products/metabolism/genetics ; Signal Transduction ; Animals ; Glycation End Products, Advanced/metabolism ; *Metabolic Diseases/metabolism ; Alzheimer Disease/metabolism ; },
abstract = {Receptor for advanced glycation end-products (RAGE) was originally identified as a receptor for advanced glycation end-products; however, it can also bind a broader range of damage-associated molecular patterns, including S100 proteins, high mobility group box 1, and amyloid-β. Ligand-induced RAGE activation promotes receptor oligomerization and recruitment of diaphanous-related formin-1, which activates several intracellular cascades, leading to the production of inflammatory mediators and reactive oxygen species. RAGE expression is upregulated in disease-associated tissues, including adipose tissue in diabetes and microglia and neurons in Alzheimer's disease, and the mechanisms by which RAGE activation contributes to pathogenesis are disease-specific. The review summarizes the expression and activation of RAGE, and the potential mechanisms through which RAGE contributes to disease pathogenesis. We further discuss current and emerging strategies for modulating RAGE signaling and highlight their therapeutic potential in the prevention and treatment of RAGE-associated diseases.},
}

Humans
*Receptor for Advanced Glycation End Products/metabolism/genetics
Signal Transduction
Animals
Glycation End Products, Advanced/metabolism
*Metabolic Diseases/metabolism
Alzheimer Disease/metabolism

@article {pmid42870413,
year = {2026},
author = {Saengsomsuan, N and Sangkakit, L},
title = {Low-Volume Superior Trunk and Superficial Cervical Plexus Block With Sedation as the Sole Regional Anesthetic for Proximal Humerus Fracture Fixation in a Patient With Alzheimer Disease.},
journal = {The American journal of case reports},
volume = {27},
number = {},
pages = {e954296},
doi = {10.12659/AJCR.954296},
pmid = {42870413},
issn = {1941-5923},
mesh = {Humans ; Female ; Aged ; *Cervical Plexus Block/methods ; *Fracture Fixation, Internal ; *Alzheimer Disease/complications ; *Shoulder Fractures/surgery/complications ; Bupivacaine/administration & dosage ; Hypnotics and Sedatives ; Geriatric Anesthesia ; Anesthetics, Local/administration & dosage ; },
abstract = {BACKGROUND Proximal humerus open reduction and internal fixation (ORIF) is usually performed under interscalene brachial plexus block (ISB) or general anesthesia (GA). ISB causes ipsilateral phrenic nerve paresis in nearly all patients, and GA may raise the risk of postoperative neurocognitive disorders in elderly patients with cognitive impairment. We report the feasibility of a low-volume regional technique, used as the sole regional anesthetic with sedation, in a patient in whom GA avoidance was desirable. CASE REPORT A 68-year-old woman (American Society of Anesthesiologists physical status II) with Alzheimer's disease underwent ORIF of a closed right proximal humerus fracture via a deltopectoral approach under superior trunk block (STB) with 5 mL of 0.5% bupivacaine, combined with superficial cervical plexus block (SCPB) with 3 mL of 0.5% bupivacaine, totaling 8 mL, with propofol and dexmedetomidine sedation. Surgery lasted 174 minutes without intraoperative rescue analgesia. Heart rate ranged from 48 to 68 beats/min during dexmedetomidine infusion without anticholinergic treatment, and oxygen saturation remained at 100% with spontaneous ventilation preserved. The block provided analgesia for about 12 hours, with pain score 1/10 at rest at 24 hours, and satisfaction 10/10. No clinically evident respiratory compromise, Horner's syndrome, or postoperative delirium was observed, although diaphragmatic and cognitive function were not formally assessed. The patient was discharged on postoperative day 2. CONCLUSIONS In this single patient, low-volume STB combined with SCPB was a feasible sole regional anesthetic technique, supported by sedation, for proximal humerus ORIF, completed without conversion to GA or clinically evident respiratory compromise. Respiratory and cognitive outcomes were clinically uneventful but not formally measured; broader utility remains to be established.},
}

Humans
Female
Aged
*Cervical Plexus Block/methods
*Fracture Fixation, Internal
*Alzheimer Disease/complications
*Shoulder Fractures/surgery/complications
Bupivacaine/administration & dosage
Hypnotics and Sedatives
Geriatric Anesthesia
Anesthetics, Local/administration & dosage

@article {pmid42870580,
year = {2026},
author = {Wang, S and Hu, T and He, M and Qin, M and Hu, Y and Zhao, L and Qin, Z},
title = {Cross-tissue graph attention networks for semi-supervised gene expression prediction.},
journal = {Briefings in bioinformatics},
volume = {27},
number = {5},
pages = {},
pmid = {42870580},
issn = {1477-4054},
mesh = {Graph Neural Networks ; Humans ; *Alzheimer Disease/genetics/metabolism ; *Gene Expression Profiling/methods ; Algorithms ; *Gene Expression ; *Computational Biology/methods ; Brain/metabolism ; },
abstract = {High-throughput biotechnologies have significantly advanced precision medicine by enabling the exploitation of global gene expression patterns to enhance our understanding of disease etiology, progression, and treatment options. However, the tissue-specific nature of gene expression presents a challenge, particularly for less accessible tissues such as the brain, underscoring the need for computational methods to accurately impute gene expression in these critical but hard-to-reach tissues. While several attempts to impute gene expression in tissue-specific contexts have shown promising results, their reliance on regression analysis faces limitations due to the inability to capture complex, nonlinear relationships in gene expression patterns. In contrast, modern machine learning techniques, particularly graph neural networks, have demonstrated superior performance by efficiently modeling the intricate interactions among genes across different tissues. Therefore, we introduce gene expression imputation with graph attention networks (gemGAT), a novel approach leveraging GATs to enhance gene expression prediction across different tissues. gemGAT distinguishes itself by predicting the expression of all genes simultaneously, utilizing the full spectrum of genomic data to account for gene coexpressions and nonlinear relationships. Validated through extensive experiments with Genotype-Tissue Expression data and a case study from the Alzheimer's Disease Neuroimaging Initiative, gemGAT demonstrates superior performance over existing methods by efficiently capturing nonlinear gene coexpressions. This advancement underscores gemGAT's potential to significantly contribute to precision medicine, showcasing its utility in advancing our understanding of gene expression in less accessible tissues.},
}

Graph Neural Networks
Humans
*Alzheimer Disease/genetics/metabolism
*Gene Expression Profiling/methods
Algorithms
*Gene Expression
*Computational Biology/methods
Brain/metabolism

@article {pmid42870749,
year = {2026},
author = {Vossberg, DAF and Rolfes, V and Fangerau, H and Haupt, M},
title = {Medical Decision-Making Capacity in Early-Stage Alzheimer Patients: Comparison With Healthy Controls and Benefit of Assistive Information.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {6},
pages = {e70227},
pmid = {42870749},
issn = {1479-8301},
support = {2020-1061//Alzheimer Society of Germany (Deutsche Alzheimer Gesellschaft)/ ; },
mesh = {Humans ; *Alzheimer Disease/psychology/diagnosis ; Female ; Male ; *Decision Making ; Aged ; *Mental Competency/psychology ; *Informed Consent/psychology ; Aged, 80 and over ; Case-Control Studies ; Neuropsychological Tests ; *Audiovisual Aids ; },
abstract = {BACKGROUND: Early-stage Alzheimer Disease (AD) may lead to restricted decision-making capacity and without standardized instruments, there is great variability in determining patients' ability to give consent. This study aimed to assess decision-making capacity of AD patients in comparison to a healthy control group and investigated the usefulness of visual aids.

METHODS: A group of 30 ad patients and 30 healthy controls were compared using the MacArthur Competence Assessment Tool for Treatment (MacCAT-T). Additionally, we implemented a modified version of the MacCAT-T with visual aids.

RESULTS: Results revealed a significant difference in the MacCAT-T domain of Understanding between the AD and control group after adjustment for age, sex, and education. No significant differences were found for Appreciation, Reasoning, or Expression of Choice. Adding visual aids led to no significant improvements.

CONCLUSIONS: Standardized assessments can be valuable tools for determining the decision-making capacity of patients with early-stage AD. The efficacy of visual aids should be further investigated.},
}

Humans
*Alzheimer Disease/psychology/diagnosis
Female
Male
*Decision Making
Aged
*Mental Competency/psychology
*Informed Consent/psychology
Aged, 80 and over
Case-Control Studies
Neuropsychological Tests
*Audiovisual Aids

@article {pmid42872064,
year = {2026},
author = {Cai, W and Yi, Y and Zeng, R and Yin, Y and Zhao, J and Zhang, J and Fu, G and Xu, H},
title = {HMGB1 functional plasticity in neurodegenerative diseases and its translational implications.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1928641},
pmid = {42872064},
issn = {1664-3224},
mesh = {Humans ; *HMGB1 Protein/metabolism/genetics ; *Neurodegenerative Diseases/metabolism ; Animals ; Translational Research, Biomedical ; Signal Transduction ; Alarmins/metabolism ; Biomarkers ; },
abstract = {High mobility group box 1 (HMGB1) is a chromatin-associated protein that can be redistributed and released during cellular stress, when it acts as an extracellular alarmin within the broader family of damage-associated molecular patterns (DAMPs). Its functions depend on subcellular localization, redox and post-translational modification state, cellular source, mode of release, and molecular partners. This critical narrative review examines how these variables shape HMGB1 biology in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), spinocerebellar ataxias (SCAs), frontotemporal dementia (FTD), and related disorders, and considers their implications for biomarker and therapeutic development. Intracellular HMGB1 contributes to chromatin organization, DNA repair, mitochondrial genome maintenance, and proteostasis. After redistribution and release, extracellular HMGB1 signals through receptors including the receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4), interacts with disease-associated proteins, and links proteostatic stress with glial activation, neuronal dysfunction, and blood-brain barrier impairment. Across disease models, two recurrent patterns emerge: loss or sequestration of intracellular HMGB1 in models of polyglutamine disorders, including HD and SCAs, and extracellular HMGB1 signaling as a progression-associated inflammatory amplifier in AD, PD, and ALS models. Central-peripheral inflammatory communication and cell-specific HMGB1 release further shape these responses. Clinical studies have associated total HMGB1 or anti-HMGB1 autoantibodies with clinical features, but current assays do not resolve redox form, cellular source, or biological activity. Most therapeutic studies remain preclinical, while available human intervention studies involve drugs with multiple molecular actions. Clinical translation requires redox-resolved and standardized assays, longitudinal human sampling, compartment- and cell-specific causal studies, and interventions with documented target engagement, central nervous system exposure, and long-term safety. HMGB1 is best understood as a context-dependent mediator rather than a uniformly pathogenic factor or a single treatment target.},
}

Humans
*HMGB1 Protein/metabolism/genetics
*Neurodegenerative Diseases/metabolism
Animals
Translational Research, Biomedical
Signal Transduction
Alarmins/metabolism
Biomarkers

@article {pmid42872207,
year = {2026},
author = {Wang, M and VanderVeen, B and Xu, ZA and Xu, Y and Mintzer, J and Murphy, A and Zhang, Q and Xu, P},
title = {Reverse the progression of Alzheimer's disease through Nano-ERASER-based adult neuroregeneration.},
journal = {Cell biomaterials},
volume = {},
number = {},
pages = {},
pmid = {42872207},
issn = {3050-5623},
support = {P30 GM154632/GM/NIGMS NIH HHS/United States ; R01 AG054839/AG/NIA NIH HHS/United States ; R01 CA263747/CA/NCI NIH HHS/United States ; R41 AG087769/AG/NIA NIH HHS/United States ; },
abstract = {Alzheimer's disease (AD) remains irreversible largely because the adult brain cannot replace lost neurons. Here, we present a Nano-ERASER-based Trim-Away system (TN-PTBP1) that enables adult neuroregeneration in the AD brain, offering a new strategy to counteract AD progression. TN-PTBP1 penetrates the blood-brain barrier, delivers anti-PTBP1 antibodies into astrocytes, and triggers rapid TRIM21-mediated PTBP1 degradation. This non-genomic protein depletion induces astrocyte-to-neuron conversion, generates functional neurons in vitro and in human brain organoids, and restores hippocampal neurogenesis in AD mice. Importantly, TN-PTBP1 treatment significantly improves cognition, learning, and memory, demonstrating true functional reversal of AD-associated deficits. By resolving the long-standing controversy surrounding PTBP1 reprogramming and establishing a translational biomaterials-based platform for in situ neuronal regeneration, this work introduces a transformative therapeutic paradigm aimed not only at slowing AD but at rebuilding the neuronal circuitry it destroys.},
}

@article {pmid42872450,
year = {2026},
author = {Kang, K},
title = {Bilateral Lower Extremity Edema During Donepezil Treatment: A Case Report.},
journal = {Current drug safety},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115748863527540260928113823},
pmid = {42872450},
issn = {2212-3911},
abstract = {Introduction/ Background: Acute bilateral lower-extremity edema is uncommon and often results from medication side effects, acute heart failure, nephrotic syndrome, or bilateral deep vein thrombosis. Drugs such as dihydropyridine calcium channel blockers, corticosteroids, thiazolidinediones, and nonsteroidal anti-inflammatory agents are known to cause edema. Donepezil, a widely used acetylcholinesterase inhibitor for Alzheimer's disease, has not been previously linked to leg edema. Recognizing rare adverse reactions is essential for patient safety, as edema may indicate serious conditions. Case Presentation: A 75-year-old woman with Alzheimer's disease developed bilateral pitting lower leg edema six months after starting treatment with donepezil. She had no history of cardiac, renal, hepatic, or venous diseases. Laboratory tests, electrocardiography, chest X-ray, and computed tomography venogram were normal, except for mild anemia and a slightly reduced estimated glomerular filtration rate. The edema resolved three weeks after discontinuation and did not recur after the administration of rivastigmine. Conclusion: The temporal association and resolution upon drug cessation suggest a probable association. Possible mechanisms may include cholinergic-induced vasodilation, which increases capillary permeability.},
}

@article {pmid42872643,
year = {2026},
author = {Patel, R and Sinha, S and Shukla, KS and Singh, B and Ved, A and Kumar, A and Yadav, N and Singh, V},
title = {Therapeutic Significance of Natural vs. Synthetic Coumarins in Alzheimer's Disease.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575482030261005073306},
pmid = {42872643},
issn = {1875-5607},
abstract = {INTRODUCTION/OBJECTIVE: Coumarin, a naturally occurring aromatic compound bearing a benzopyrone scaffold, represents a versatile motif in synthetic drug design. Recent therapeutic developments have highlighted its potential as a privileged pharmacophore for neurodegenerative disorders (NDs), with particular efficacy targeting Alzheimer's disease (AD). This study presents a critical, comparative review of natural versus synthetic coumarins, evaluating their neuroprotective mechanisms across various preclinical, non-transgenic models of sporadic Alzheimer's disease (sAD).

METHODS: Natural coumarins (e.g., umbelliferone, esculetin, and scopoletin) exert potent antioxidant, anti-inflammatory, and moderate enzyme-inhibitory activities, particularly against acetylcholinesterase (AChE) and β-amyloid (Aβ) aggregation. These phytochemicals attenuate neurodegeneration by modulating oxidative stress and neuroinflammatory pathways across various cellular and rodent models, including 5xFAD mice, as well as streptozotocin (STZ)-and scopolamine (SCOP)- induced Alzheimer's disease (AD) rat models. However, their clinical utility remains constrained by poor bioavailability and modest potency. To address these limitations, synthetic coumarin derivatives, including coumarin-pyrrolidine, coumarin-triazole, coumarin-chalcone, and coumarin-donepezil hybrids, as well as hydroxycoumarins, have been developed. These heterocyclic hybrid architectures exhibit superior therapeutic potency, enhanced blood-brain barrier (BBB) permeability, and synergistic inhibition of core pathological targets, including AChE activity and Aβ aggregation.

RESULT: Both in vivo preclinical models and in silico docking simulations substantiate the neuroprotective capacity of coumarin-based frameworks, demonstrating substantial cognitive rescue, restored synaptic plasticity, and favorable safety margins. Moving beyond the baseline safety of naturally derived coumarins, structural optimization and hybrid design strategies serve as a compelling framework for developing potent, multi-target therapeutics for neurodegenerative diseases.

DISCUSSION: According to the review, Alzheimer's disease treatment is shifting from natural coumarins to multi-target-directed ligands (MTDLs) because natural compounds, such as esculetin, scopoletin, and daphnetin, are often limited by narrow target specificity and lower potency than synthetic coumarin derivatives.

CONCLUSION: Herein, the authors review the biological activities of natural coumarins and their synthetic analogs as potential therapeutics for Alzheimer's disease (AD). This study systematically compared and evaluated the therapeutic efficacy and structural scaffold variations of both natural and synthetic derivatives. To support their translational potential, this study also summarizes current ADMET profiles and pharmacokinetic evaluations, which represent key prerequisites for clinical advancement.},
}

@article {pmid42872646,
year = {2026},
author = {Budak Savaş, A and Yeşilyurt, F and Hacimuftuoglu, A},
title = {From Hypothesis to Clinical Validation: A Bibliometric Mapping of Immunotherapy for Neurodegenerative Proteinopathies (2000-2025).},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273531307261012100737},
pmid = {42872646},
issn = {1996-3181},
abstract = {INTRODUCTION/OBJECTIVE: For twenty-five years, despite persistent challenges, the field of neurodegenerative disease has remained committed to a single hypothesis: targeting the immune system directly against misfolded proteins accumulating in the brain. Today, this approach has produced a clinical counterpart, with three monoclonal antibodies now approved, although the field is still progressing toward clinical validation. However, the research lines, countries, institutions, and journals through which this point was reached, and how far that validation has actually progressed, have remained largely unexamined.

METHODS: This study analyzes 9,863 articles published between 2000 and 2025 using bibliometric methods to map the field's intellectual structure, productivity patterns, and the thematic evolution shaped around four turning points.

RESULTS: The findings reveal a nonlinear trajectory. Annual output rose from a steady pace in the early 2000s to a sudden surge after 2019, exceeding 900 publications per year. Research output is heavily concentrated in the United States, while impact is concentrated among a small number of core journals and prolific authors. Only 47 journals account for one-third of the literature, and roughly four out of five authors have contributed only a single publication to the field. While the amyloid hypothesis continues to rest on strong genetic foundations, which protein species is actually neurotoxic, soluble oligomers or deposited plaques, remains an open question, and this keeps alive the debate over what clinical trials are truly measuring. The safety of approved drugs, particularly ARIA-related imaging abnormalities, and the challenge of delivering treatment across the blood-brain barrier stand out as fronts the field has yet to overcome.

DISCUSSION: Perhaps the most notable signal is that this accumulated progress now appears to be extending beyond Alzheimer's disease: thematic patterns suggest the same immunotherapeutic logic is beginning to extend toward Parkinson's disease and other proteinopathies.

CONCLUSION: The study presents, within a single framework, the critical periods the field has passed through, who has led this journey, and which questions remain unanswered.},
}

@article {pmid42872652,
year = {2026},
author = {Watson, D and Neam, MG and Stafford, M and Bouchard, C and Ranney, V and Werner, S},
title = {Transitioning from Clinical Trial to Clinical Practice for Long-Term Lecanemab Treatment in Early Alzheimer's Disease: Perspectives from a Cohort Study from the Alzheimer's Research and Treatment Center.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050525938260923072703},
pmid = {42872652},
issn = {1875-5828},
abstract = {INTRODUCTION/BACKGROUND: Lecanemab, an anti-amyloid monoclonal antibody, significantly reduces amyloid markers and slows clinical decline in early Alzheimer's disease (AD) clinical trials. We assessed our single-center experience with lecanemab, including evaluating efficacy and safety data as well as patient-reported outcomes of individuals from our single center treated with intravenous or subcutaneous lecanemab.

MATERIALS AND METHODS: We conducted a single-center, nested cohort study of early AD subjects on lecanemab (intravenous or subcutaneous) at our center. Participants had been initiated on lecanemab therapy as part of lecanemab Study 201 or Clarity AD, and then continued lecanemab treatment in our center. Data collection included patient demographic characteristics, efficacy (eg, CDR-SB), safety, and patient-reported outcomes from surveys.

RESULTS: At our center, 136 people were randomized to receive either lecanemab or placebo in either lecanemab Study 201 (lecanemab:53; placebo:16) or Clarity AD (lecanemab:37; placebo:30). Patients receiving lecanemab were more likely to have higher rates of stable or improved disease across efficacy assessments relative to placebo. There were no new long-term safety signals, and the most common adverse events for lecanemab patients were infusion-related reactions (36.2%), ARIA-H (25.9%), and ARIA-E (13.8%). Survey responses demonstrated high satisfaction with the subcutaneous lecanemab administration, including with treatment satisfaction (97%) and convenience (97%). All patients preferred subcutaneous over IV dosing, citing quickness, ease, and comfort.

DISCUSSION: Our single-center experience with long-term lecanemab treatment was similar to that observed in clinical trials.

CONCLUSION: The subcutaneous lecanemab formulation was highly preferred by patients and care partners, with feedback highlighting reduced treatment burden and strong acceptability.},
}

@article {pmid42872679,
year = {2026},
author = {Li, M and Lv, S and Cui, L and Fang, S},
title = {Tetrachloro-1,4-benzoquinone Exerts Neurotoxicity through Neuroinflammation and the TLR4 Signaling Pathway, which is a Risk Factor for Alzheimer's Disease: An Integrated Network and Mendelian Randomization Analysis.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050502048260925094031},
pmid = {42872679},
issn = {1875-5828},
abstract = {INTRODUCTION: Research has found that the disinfection byproduct Tetrachloro-1,4- Benzoquinone (TCBQ) in drinking water increases the risk of Alzheimer's Disease (AD). However, the mechanism by which TCBQ increases the risk of AD remains unclear.

METHODS: This study employs a comprehensive approach that includes network toxicology (PPI network, hub genes, KEGG analysis), Mendelian randomization, computational simulations (molecular docking and dynamics), and cellular experiments to systematically elucidate the neurotoxic mechanisms of TCBQ.

RESULTS: Key findings indicate that TCBQ induces neurotoxicity by activating the Toll-like receptor signaling pathway, AD, and the apoptosis pathway. All ligand-receptor docking energies are recorded at ≤ -1.8 kcal/mol, suggesting that TCBQ demonstrates a stable interaction with the targets. Molecular simulations confirm that TCBQ tightly binds to targets such as Caspase3 and TLR4. Mendelian randomization found that XDH, FABP3, IMPDH1, ACBD7, and CASP3 are common targets and play a potential role in AD. Immunofluorescence experiments revealed that APP expression increased after TCBQ treatment. Cellular experiments verified that TCBQ significantly upregulates the expression of inflammation- and apoptosis-related proteins, including IL-1B, MyD88, NFκB, TLR4, Cleaved-Caspase3, and Cyt C, leading to neuronal cell death. Notably, the TLR4 inhibitor effectively reversed the expression of these proteins and alleviated cell death.

DISCUSSION: The discussion indicates that TCBQ induces neurotoxicity by activating the TLR4 pathway and apoptotic signals, and Caspase3 is a potential co-target. TLR4 inhibitors can reverse protein alterations and cell death, suggesting that intervention in this pathway may alleviate TCBQrelated nerve damage.

CONCLUSION: Our research provides a theoretical basis for the clinical assessment of potential neurotoxicity risks in populations exposed to TCBQ.},
}

@article {pmid42873344,
year = {2026},
author = {Lee, M and Lee, S and Kim, JH and Oh, MS},
title = {Rheum undulatum Linné Exerts Neuroprotective Effects Against Aβ Oligomer-Induced Neuronal Damage by Modulating p53-Mediated Signaling.},
journal = {Neurochemical research},
volume = {51},
number = {5},
pages = {},
pmid = {42873344},
issn = {1573-6903},
support = {RS-2023-KH138733//Korea Health Industry Development Institute/ ; RS-2023-KH138733//Korea Health Industry Development Institute/ ; RS-2023-KH138733//Korea Health Industry Development Institute/ ; RS-2023-KH138733//Korea Health Industry Development Institute/ ; },
mesh = {Animals ; *Amyloid beta-Peptides/toxicity ; *Neuroprotective Agents/pharmacology/therapeutic use/isolation & purification ; *Signal Transduction/drug effects/physiology ; *Tumor Suppressor Protein p53/metabolism ; *Rheum/chemistry ; *Neurons/drug effects/metabolism ; Mice ; Male ; Peptide Fragments/toxicity ; Mice, Inbred C57BL ; *Plant Extracts/pharmacology/therapeutic use ; Hippocampus/drug effects/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and synaptic dysfunction. Accumulating evidence indicates that β-amyloid oligomers (AβO), the most neurotoxic form of β-amyloid, play a critical role in the pathogenesis of AD by inducing synaptic loss, neuronal death, and neuroinflammation. Therefore, targeting AβO-driven pathological processes through multi-target therapeutic strategies represents a promising approach to treating AD. This study aimed to investigate the neuroprotective effects of Rheum undulatum Linné rhizome (RUL) and the underlying mechanisms of its action against AβO-induced neurotoxicity using integrated in vitro, in vivo, and in silico approaches. RUL treatment protected HT22 and N2a neuronal cells from AβO-induced neurotoxicity and reduced extracellular AβO levels. In AβO-injected mice, oral administration of RUL alleviated memory impairment, preserved synaptic integrity, as evidenced by increased PSD95 and SYP expression, and suppressed microglial and astrocytic activation, as indicated by reduced Iba-1 and GFAP immunoreactivity in the hippocampus. Mechanistically, systems-level network analysis identified p53-related signaling as a central regulatory axis in the AD-associated pathway. These network-level insights were experimentally validated by demonstrating that RUL suppressed p53 phosphorylation, increased the BCL2/Bax ratio, inhibited caspase-3 activation, and reduced pro-inflammatory cytokines, including TNF-α and IL-1β, in the hippocampus. Collectively, these findings demonstrate that RUL exerts neuroprotective effects by preserving synaptic integrity and concurrently suppressing apoptotic and neuroinflammatory pathways through the network-level modulation of AβO-driven pathology, supporting its potential as a multi-target therapeutic candidate for AD.},
}

Animals
*Amyloid beta-Peptides/toxicity
*Neuroprotective Agents/pharmacology/therapeutic use/isolation & purification
*Signal Transduction/drug effects/physiology
*Tumor Suppressor Protein p53/metabolism
*Rheum/chemistry
*Neurons/drug effects/metabolism
Mice
Male
Peptide Fragments/toxicity
Mice, Inbred C57BL
*Plant Extracts/pharmacology/therapeutic use
Hippocampus/drug effects/metabolism

@article {pmid42873357,
year = {2026},
author = {Gündoğdu, AA and Özkan, NG and Adapınar, DÖ},
title = {The small giant actor in the pathogenesis of neurodegenerative diseases: Microtubules.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42873357},
issn = {1573-7365},
mesh = {Humans ; *Microtubules/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; tau Proteins/metabolism ; Axonal Transport/physiology ; },
abstract = {Neurodegenerative diseases are a clinically and pathologically diverse group of disorders characterized by progressive neuronal dysfunction, synaptic impairment, and neuronal loss. Although research has traditionally focused on disease-associated protein misfolding and aggregation, increasing evidence implicates abnormalities of cytoskeletal organization and intracellular transport in several neurodegenerative conditions. Microtubules contribute to neuronal polarity, axonal and dendritic transport, organelle distribution, and synaptic maintenance. These functions are regulated in part by tubulin isotypes, post-translational modifications collectively described as the tubulin code, microtubule-associated proteins, and molecular motors. This narrative review examines evidence linking alterations in these processes with Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, and prion disease. We summarize proposed interactions among microtubule instability, impaired axonal transport, mitochondrial dysfunction, and disease-associated proteins, including tau, α-synuclein, mutant huntingtin, TDP-43, and prion protein. Evidence connecting tau pathology with microtubule dysfunction is comparatively well established in Alzheimer's disease and MAPT-related tauopathies, whereas findings in other disorders are more heterogeneous and are frequently derived from cellular or animal models. We also discuss emerging experimental approaches, candidate biomarkers, and investigational microtubule-directed treatments. However, no tubulin-specific biomarker or microtubule-targeted disease-modifying treatment discussed in this review has yet been clinically validated. Overall, microtubule dysfunction may represent one component of broader, disease-specific pathological networks rather than a universal primary cause of neurodegeneration. Further longitudinal and clinical studies are needed to determine whether microtubule-related alterations act as causes, consequences, or modifiers of disease progression.},
}

Humans
*Microtubules/metabolism/pathology
*Neurodegenerative Diseases/metabolism/pathology
Animals
tau Proteins/metabolism
Axonal Transport/physiology

@article {pmid42874179,
year = {2026},
author = {Qu, L and Wang, Y and Ren, L and Zhang, C and Guo, Z and Zhang, L and Pang, X and Sha, S},
title = {Advancing early detection of Alzheimer's disease: from established biomarkers to future innovations.},
journal = {International immunopharmacology},
volume = {190},
number = {},
pages = {117537},
doi = {10.1016/j.intimp.2026.117537},
pmid = {42874179},
issn = {1878-1705},
abstract = {Alzheimer's disease (AD) is a major form of dementia, imposes an escalating global burden on public health and social care. Pathological changes in AD occur years before clinical symptoms, defining a prolonged preclinical phase. Currently, there is no effective treatment exist for late-stage AD, making early diagnosis and intervention indispensable, in which biomarkers play a pivotal role. While cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers improved AD diagnostic accuracy, their clinical application is limited by invasiveness, high costs. Advances in ultrasensitive immunoassay technologies has rendered peripheral blood biomarkers easily accessible, cost-effective, minimally invasive, and suitable for continuous monitoring, offering noval opportunities for AD screening, diagnosis and progression tracking. Additionally, non-invasive body fluids including saliva, urine and tears are being explored as potential biomarkers. Artificial intelligence (AI)-driven multimodal fusion, integrated with large-scale multimodal computing frameworks, significantly improve the accuracy of early AD diagnosis. Recent studies have identified a series of promising synaptic and neuronal biomarkers, such as neurofilament light chain (NFL), neurogranin (Ng), β-secretase 1 (BACE1) and synaptosomal-associated protein 25 (SNAP-25). Inflammatory mediators and genetic factors also contribute to AD pathological evaluation. This review systematically characterizes biomarker profiles of emerging non-invasive carriers (saliva, urine and tears). It further synthesizes cohort-derived quantitative diagnostic metrics (AUC, sensitivity, specificity) of multimodal AD biomarkers and conducts head-to-head comparison to clarify their respective strengths and translational limitations, aiming to provide evidence-based insights for optimizing early AD screening and diagnostic strategies.},
}

@article {pmid42874425,
year = {2026},
author = {Le Scouarnec, L and Bouteloup, V and Grasset, L and Planche, V and Chêne, G and Dufouil, C and , },
title = {Estimating the eligible population for amyloid-targeting monoclonal antibody therapy in memory clinics: Application to lecanemab in France.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {10},
pages = {100683},
doi = {10.1016/j.tjpad.2026.100683},
pmid = {42874425},
issn = {2426-0266},
abstract = {Lecanemab was the first amyloid-targeting monoclonal antibody approved by the European Commission for treating patients with mild cognitive impairment (MCI) and mild dementia due to Alzheimer's disease (AD). While this marketing authorization led to heterogeneous situations across European countries, France declined reimbursement, citing limited clinical benefit and concerns about the healthcare system's capacity to implement this new care pathway. This capacity depends directly on the number of eligible patients, yet robust estimates remain limited and highly variable across studies. Our objective was therefore to estimate the population eligible for lecanemab in France. Using transportability methods based on inverse odds of selection weighting, we articulated the nationwide consultation data from the French National Alzheimer Database (BNA) with the deeply phenotyped MEMENTO clinical cohort. Eligibility for lecanemab followed the French appropriate use recommendations: 1) clinical eligibility (age 50-90 years, MCI with common AD phenotype or mild AD dementia, MMSE ≥22), 2) biological eligibility (amyloid confirmation determined sequentially using plasma p-tau217, cerebrospinal fluid biomarkers and amyloid-PET), 3) absence of contraindications (APOEε4 homozygosity, anticoagulant use, MRI risk markers for ARIA). Among patients consulting French memory clinics, 19.5% met clinical eligibility criteria. Of these, 73.0% (95%CI: 67.6-77.9) were amyloid-positive, and 49.7% (95%CI: 44.0-55.5) remained eligible after applying safety criteria. Overall, 9.7% (95%CI: 8.6-10.8) of patients consulting memory clinics were estimated to be eligible for lecanemab, representing approximately 18,200 individuals nationally (annual average, 2022-2024). These results inform healthcare planning for disease-modifying therapy implementation in France and comparable countries.},
}

@article {pmid42874747,
year = {2026},
author = {Xiao, X and Gao, F and Xie, J and Lu, Y and Lv, K and Mo, H and Chen, J and Liu, J and Meng, Q and Guan, Y and Chen, Q},
title = {Fucosylated Chondroitin Sulfate Modulates Microglia-Associated Responses and Reduces Aβ Burden with ERK1/2-Related Signaling Changes.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106278},
doi = {10.1016/j.neuint.2026.106278},
pmid = {42874747},
issn = {1872-9754},
abstract = {INTRODUCTION: Fucosylated chondroitin sulfate (FCS) is a sulfated polysaccharide derived from the marine organism Apostichopus japonicus. This study aimed to investigate its neuroprotective potential, specifically focusing on microglial modulation and ERK1/2 signaling, in Alzheimer's disease (AD) models.

METHODS: An integrated in vitro and in vivo approach was employed. In vitro, Aβ42-stimulated BV2 microglia were treated with FCS, and the broad protein kinase C activator TPA was used as a pharmacological perturbation to examine whether the FCS-associated ERK1/2 signaling changes were reversible. Cytokine levels, microglial phenotype markers (CD86, CD206, iNOS, Arg-1), Aβ handling, and MAPK pathway proteins (p-ERK1/2, p38, JNK) were analyzed. In vivo, 5xFAD transgenic mice received intraperitoneal FCS for 28 days. Aβ plaque burden, soluble/insoluble Aβ levels, cognitive performance (Morris water maze, Y-maze), cortical Iba1-positive cell counts, activation state (Iba1[+]CD86[+], Iba1[+]CD206[+]), and expression of p-ERK1/2, iNOS, and Arg-1 were assessed.

RESULTS: In vitro, FCS attenuated Aβ42-induced pro-inflammatory responses (reduced IL-6, TNF-α; increased IL-10), modulated phenotype (decreased CD86/iNOS; increased CD206/Arg-1), and increased the cell-associated Aβ fraction while reducing supernatant Aβ. FCS reduced Aβ42-associated ERK1/2 phosphorylation and the nuclear-to-cytoplasmic p-ERK1/2 fluorescence signal ratio, and these changes were partially attenuated by TPA. In vivo, FCS treatment reduced cerebral Aβ burden, improved spatial and working memory, decreased the number and proportion of cortical Iba1[+]CD86[+] microglia, and increased the Iba1[+]CD206[+] subset. Cortical p-ERK1/2/total ERK1/2 and iNOS expression were downregulated, while Arg-1 was upregulated.

CONCLUSION: FCS reduced Aβ-related pathological burden, improved selected behavioral outcomes, and modulated microglia-associated inflammatory and phenotype-related readouts in AD models. These effects were accompanied by ERK1/2-related signaling changes, supporting a pathway-associated interpretation rather than definitive proof of ERK1/2 causality in vivo.},
}

@article {pmid42875627,
year = {2026},
author = {Hwang, J and Delman, BN and Naasan, G},
title = {Intracranial metastasis as a mimic of amyloid-related imaging abnormalities.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {11},
pages = {},
pmid = {42875627},
issn = {1590-3478},
mesh = {Humans ; Female ; *Brain Neoplasms/secondary/diagnostic imaging ; Aged ; Diagnosis, Differential ; *Thyroid Neoplasms/pathology/diagnostic imaging ; Carcinoma, Papillary/diagnostic imaging ; *Alzheimer Disease/diagnostic imaging/drug therapy ; Brain Edema/diagnostic imaging ; Magnetic Resonance Imaging ; Brain/diagnostic imaging ; Amyloid/metabolism ; },
abstract = {This report describes a 79-year-old woman with biomarker-confirmed Alzheimer's disease who developed progressive vasogenic edema initially interpreted as amyloid-related imaging abnormalities (ARIA) with edema during lecanemab therapy, but was ultimately found to have multifocal intracranial metastases from recurrent papillary thyroid carcinoma. The serial neuroimaging highlights the diagnostic challenge of distinguishing ARIA from alternative causes of vasogenic edema in the era of anti-amyloid monoclonal antibody treatment. In addition, this case raises an important and underexplored question regarding whether anti-amyloid therapies may alter blood-brain barrier integrity in a manner that could influence metastatic spread in susceptible patients.},
}

Humans
Female
*Brain Neoplasms/secondary/diagnostic imaging
Aged
Diagnosis, Differential
*Thyroid Neoplasms/pathology/diagnostic imaging
Carcinoma, Papillary/diagnostic imaging
*Alzheimer Disease/diagnostic imaging/drug therapy
Brain Edema/diagnostic imaging
Magnetic Resonance Imaging
Brain/diagnostic imaging
Amyloid/metabolism

@article {pmid42875646,
year = {2026},
author = {Kumar, A},
title = {Synergistic approaches to Alzheimer's disease: exploring the combined efficacy of phytoconstituents and conventional drugs.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42875646},
issn = {1568-5608},
abstract = {BACKGROUND: Cognitive functions deteriorate with Alzheimer's disease (AD), a kind of degenerative disease. Problems with memory, interpersonal interactions, problem-solving, and other cognitive functions that limit a person's ability to do daily tasks are the hallmarks of dementia. This condition affects about 50 million individuals globally. Traditional therapies for AD, like galantamine, donepezil, and memantine, only offer symptomatic alleviation through glutamatergic regulation and cholinergic augmentation, making AD a significant worldwide health concern.

OBJECTIVE: This review assesses the possibility of improving the effectiveness of therapy by combining significant phytoconstituents with traditional AD therapies.

METHODS: A complete literature review was carried out using peer-reviewed publications, experimental investigations, and review papers published from 2010 to 2025. The primary objective of the investigation was to study the interaction between phytoconstituents and conventional therapy in the treatment of Alzheimer's disease.

RESULT: Our outcomes demonstrate the powerful multi-target adjuvant properties of curcumin, resveratrol, quercetin, berberine, and luteolin. In particular, Berberine and Quercetin considerably reduce neuroinflammation and oxidative stress through the Nrf2/HO-1 and NF-κB pathways, whereas Curcumin and resveratrol enhance the anti-amyloidogenic effects of conventional medications. Additionally, luteolin exhibits a special capacity to regulate tau hyperphosphorylation, which enhances memantine's stabilising neurotransmitter actions.

DISCUSSION: The primary objective of therapy has shifted from symptomatic relief to disease modification by the synergy between phytoconstituent and conventional drugs. These combinations preserve the structural integrity of the cholinergic synapse by concurrently mitigating oxidative stress and amyloid toxicity.

CONCLUSION: A possible paradigm shift towards holistic neuroprotection is represented by the incorporation of these five essential phytoconstituents into traditional AD regimens. To ensure clinical translatability, future research must now focus on nanoformulations that can overcome the limited bioavailability of substances like curcumin. These methods may improve treatment effectiveness, lessen adverse effects, and reduce the chance of resistance, providing a more thorough method of handling the complexities of AD.},
}

@article {pmid42875809,
year = {2026},
author = {Liu, ZP and Lee, D and Tan, Z and Wu, A and Mei, L and Xiong, WC},
title = {Levetiracetam restores GABAergic function and network homeostasis following Vps35 deficiency in excitatory neurons.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42875809},
issn = {2047-9158},
support = {AG045781/NH/NIH HHS/United States ; },
mesh = {Animals ; Mice ; *Levetiracetam/pharmacology ; *Vesicular Transport Proteins/deficiency ; *Homeostasis/drug effects/physiology ; Mice, Knockout ; *Neurons/drug effects/metabolism ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) and related dementias (ADRDs) remain incurable, partly due to their complex and poorly understood pathogenic mechanisms. Loss of vacuolar protein sorting-associated protein 35 (VPS35), a core component of the retromer complex, has been implicated in AD and ADRDs. While Vps35 deficiency is known to increase amyloidogenesis by regulating its cargo proteins, such as APP and BACE1, the precise mechanism by which VPS35 dysfunction leads to cognitive impairment remains elusive. While neuronal VPS35 regulates trafficking and functions of multiple synaptic membrane proteins, such as postsynaptic glutamatergic and GABAnergic receptors and pre-synaptic vesicle protein SV2A, and Levetiracetam (LEV), an antiepileptic drug that improves cognition, interacts with the SV2A, exactly how LEV enhances cognition is still a matter of debate.

METHODS: Given the abundant expression of VPS35 in pyramidal excitatory neurons, we generated a conditional knockout mouse model with Vps35 deletion from postnatal glutamatergic excitatory neurons (Vps35[CaMKIIα]) and characterized its phenotypes using a combination of behavioral assessments, and electrophysiological, biochemical, and immunohiotological analyses in the hippocampal CA1 region. A targeted pharmacological screen was conducted to evaluate the therapeutic potential of LEV.

RESULTS: Vps35 deletion did not disrupt the gross brain development but led to progressive cognitive decline beginning at three months of age. Electrophysiological analyses revealed earlier-onset hippocampal CA1 hyperexcitability, marked by depolarized resting membrane potentials and reduced Kir2.1 expression. However, restoring Kir2.1 to suppress hyperexcitability failed to rescue cognitive deficits. Instead, cognitive impairment was associated with weakened GABAergic transmission and disruption of the excitatory/inhibitory balance in the Schaffer collateral-CA1 circuit. Notably, LEV treatment diminished these deficits in mutant mice. Intriguingly, LEV increased the levels of retromer component, VPS26A, and multiple pre- and postsynaptic GABAergic proteins, in addition to SV2A, all of which were reduced in Vps35-deficient CA1 neurons.

CONCLUSIONS: These findings identify VPS35 in excitatory neurons as a critical factor for inhibitory synapse maintenance and network homeostasis. This study also highlights LEV as a potential therapeutic strategy for ADRDs through the preservation of GABAergic synapses.},
}

Animals
Mice
*Levetiracetam/pharmacology
*Vesicular Transport Proteins/deficiency
*Homeostasis/drug effects/physiology
Mice, Knockout
*Neurons/drug effects/metabolism

@article {pmid42876862,
year = {2026},
author = {Jiang, Y and Lin, H and Hong, B and Yue, L},
title = {Donanemab-associated clinical improvement in Alzheimer's disease presenting predominantly with neuropsychiatric symptoms: A case report.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261478025},
pmid = {42876862},
issn = {2542-4823},
abstract = {Late-life depression may mask Alzheimer's disease (AD). We report a 78-year-old man with treatment-refractory depressive and anxiety symptoms accompanied by paroxysmal somatic attacks, unresponsive to psychotropic treatment and modified electroconvulsive therapy. Ultimately, biomarker evaluation confirmed AD pathology, and donanemab was initiated. Follow-up amyloid positron emission tomography demonstrated marked amyloid clearance, particularly in the frontal lobe, accompanied by concurrent improvement in depressive symptoms, cognition, and reduced somatic attacks. This case suggests that anti-amyloid therapy may benefit AD patients presenting with refractory neuropsychiatric symptoms, potentially related to frontal amyloid clearance, underscoring the importance of AD screening in resistant late-life depression.},
}

@article {pmid42876885,
year = {2026},
author = {Hazan, J and Salemme, S and Liu, KY and Howard, R},
title = {How should the results of Alzheimer's disease treatment trials be communicated to colleagues, patients, and families?.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {4},
pages = {e70330},
pmid = {42876885},
issn = {2352-8737},
abstract = {The approval of amyloid-lowering therapies for Alzheimer's disease (AD) has increased the importance of clearly and precisely communicating complex clinical trial findings to patients, caregivers, clinicians, and the wider public. Because the clinical relevance of the modest treatment effects observed on cognitive and functional rating scales, which served as primary trial outcome measures, is uncertain and difficult to interpret, these effects have been translated into alternative quantitative interpretations, such as relative slowing of decline and time-saved estimates, and supplemented with qualitative descriptions and patient or caregiver testimonials. In this perspective, we examine the advantages and limitations of these approaches, with a particular focus on time-saved approaches, and discuss the assumptions required to move beyond reliance on directly observed primary outcome data from clinical trials. We argue that alternative methods of communicating treatment effects may improve accessibility but introduce additional uncertainty and may lead patients and clinicians to overestimate the size of benefit because they will not appreciate some of the assumptions on which these methods are based. Clear and accurate communication of treatment benefits, risks, limitations, and evidential uncertainty is essential to support informed decision making and maintain public trust in AD research and treatment.},
}

@article {pmid42876904,
year = {2026},
author = {Tagane, Y and Nakamori, M and Ishida, M and Tsuchigauchi, S and Sugimoto, T and Yamazaki, Y and Maruyama, H},
title = {Steroid-responsive inflammatory leptomeningeal encephalitis temporally associated with lecanemab therapy: A case report.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261483284},
pmid = {42876904},
issn = {2542-4823},
abstract = {Lecanemab is an anti-amyloid-β monoclonal antibody used for the treatment of early Alzheimer's disease. Herein, we report a 46-year-old woman who developed headache, fever, disorientation, and impaired consciousness 10 months after starting lecanemab. Magnetic resonance imaging revealed a small focal subcortical fluid-attenuated inversion recovery hyperintense lesion and bilateral occipital leptomeningeal enhancement without detectable hemorrhagic findings on T2*-weighted gradient-recalled echo imaging. Cerebrospinal fluid revealed mononuclear pleocytosis and markedly elevated interleukin-6. Infectious studies and neuronal surface antibodies were negative. High-dose corticosteroid therapy led to rapid clinical improvement. These findings support a diagnosis of steroid-responsive inflammatory leptomeningeal encephalitis temporally associated with lecanemab.},
}

@article {pmid42876920,
year = {2026},
author = {Nakashima, S and Sato, K and Niimi, Y and Ihara, R and Iwata, A and Nemoto, K and Arai, T and Higashi, S and Igarashi, A and Kasuga, K and Akiyama, H and Awata, S and Ikeda, M and Toda, T and Iwatsubo, T},
title = {Identifying facility-level and infrastructure-level bottlenecks in Japan's lecanemab rollout through an online survey of dementia specialists.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261470054},
pmid = {42876920},
issn = {2542-4823},
abstract = {BACKGROUND: The approval of lecanemab has created new operational demands for Alzheimer's disease care. Japan's nationwide rollout under universal health insurance offers an opportunity to identify real-world bottlenecks in treatment delivery.

OBJECTIVE: To identify facility-level and infrastructure-level factors associated with wait time to initial lecanemab infusion and treated patient volume among dementia specialists in Japan.

METHODS: We performed a secondary analysis of an anonymous online survey of 296 dementia specialists certified to prescribe lecanemab in Japan approximately one year after approval. We examined associations between physician/facility characteristics, diagnostic and infusion resources, perceived implementation barriers, and two delivery metrics: wait time from first consultation to first infusion and number of treated patients per respondent. Bayesian accelerated failure-time and zero-truncated Poisson mixed-effects models were used.

RESULTS: Approximately 80% of respondents reported average wait times of 3 months or less, whereas the median treated caseload was modest at 5 patients per physician. Perceived mismatch between treatment capacity and demand was associated with longer wait time (time ratio 1.323, 95% credible interval 1.045-1.682). Cerebrospinal fluid (CSF)-dominant amyloid-testing strategies tended to be associated with smaller caseloads, while in-house CSF testing and APOE testing were associated with larger caseloads. High-volume centers reported constrained outpatient infusion space. Lack of reimbursement for infusion-related tasks and APOE testing were perceived as major system-level barriers.

CONCLUSIONS: Japan's rollout may be constrained by some bottlenecks in diagnostics, infusion infrastructure, and uncompensated tasks. Appropriate policy interventions might help secure equitable access to the treatment.},
}

@article {pmid42877253,
year = {2026},
author = {Starr, EG and Dhaliwal, J and McLatchey, MG and Young, NP and Lai, B},
title = {Neurons on the rocks: A case of alcohol use and early onset Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261459404},
pmid = {42877253},
issn = {2542-4823},
abstract = {A 46-year-old female was admitted to the hospital for confusion, cognitive decline, and hallucinations with alcohol withdrawal. Her history was notable for Alcohol use disorder (AUD) and family history of Alzheimer's disease (AD). Comprehensive workup was unrevealing for metabolic encephalopathy, infection, or nutritional deficiencies. Phosphatidyl ethanol level was 1181, indicating severe alcohol misuse. Phospho-Tau 217 testing raised suspicion of AD and FDG-PET scan confirmed patterns consistent with early onset AD. AUD can precipitate earlier or more severe onset of AD. Phospho-Tau 217 can be a useful screening marker to identify people at risk of AD to prompt intensive treatment.},
}

@article {pmid42877265,
year = {2026},
author = {Yajima, R and Ishiguro, T and Michikawa, M and Naruse, S},
title = {Caregiver burden, not patient cognitive impairment, predicts adherence to donepezil transdermal patch in Alzheimer's disease: A retrospective real-world study.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261468306},
pmid = {42877265},
issn = {2542-4823},
abstract = {BACKGROUND: The donepezil transdermal patch is a useful option for Alzheimer's disease (AD) patients with poor oral adherence. However, treatment discontinuation due to skin irritation or management difficulties remains a clinical challenge.

OBJECTIVE: To identify predictive factors for the successful continuation of the donepezil transdermal patch in a real-world setting.

METHODS: A retrospective review included 26 AD patients newly prescribed or switched to the donepezil patch at a dementia center. Patients were divided into continuation (n = 15) and discontinuation (n = 11) groups based on a 12-week cutoff. We evaluated baseline demographics, Mini-Mental State Examination (MMSE), Clinical Dementia Rating-Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale for Activities of Daily Living (ADL-Cog), and caregiver burden using the 8-item Zarit Burden Interview (Zarit-8). Multivariate logistic regression identified risk factors for discontinuation.

RESULTS: Univariate analysis showed no significant differences between groups in age (p = 0.855), MMSE (p = 0.677), CDR-SB (p = 0.762), and ADL-Cog (p = 0.826). Although the mean Zarit-8 score was higher in the discontinuation group (14.00 ± 10.70 versus 7.86 ± 5.55, p = 0.171), this lacked statistical significance. However, multivariate regression revealed a higher Zarit-8 score was a significant independent predictor of discontinuation after adjusting for age (p = 0.038, OR = 1.134).

CONCLUSIONS: Caregiver burden, rather than patient cognitive function or impairment in activities of daily living, significantly predicts discontinuation of the transdermal patch. To the best of our knowledge, no previous studies have utilized the Zarit burden scale as a clinical predictor of pharmacological adherence. Assessing caregiver reserve before introduction is crucial for maintaining adherence.},
}

@article {pmid42877307,
year = {2026},
author = {Imamura, J},
title = {Pre-pilot study: Reactivating brain waste clearance via vasopressin fragment-A novel approach to Alzheimer's disease therapy.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261449497},
pmid = {42877307},
issn = {2542-4823},
abstract = {BACKGROUND: Impaired clearance of amyloid-β (Aβ) and other metabolic waste products has been implicated in Alzheimer's disease (AD). Arginine vasopressin (AVP) fragments have been associated with memory-related effects and may influence glymphatic-related pathways.

OBJECTIVE: This pre-pilot exploratory study investigated the potential effects of an AVP (4-9) fragment analog on Aβ-related biomarkers and cognitive function.

METHODS: Seven participants (three healthy adults and four individuals with AD) received intranasal administration of an AVP (4-9) fragment analog for two weeks at a daily dose of 60 ng. Aβ-related burden was assessed using blood-based Composite Biomarker (CB) values reported to correlate with amyloid PET findings. Cognitive function in AD participants was evaluated using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog).

RESULTS: At baseline, CB values were 5- to 20-fold higher in individuals with AD than in healthy adults. Following treatment, mean CB values in the AD group decreased by 36%, with comparable relative reductions observed across groups. ADAS-Cog scores improved by a mean of 8.1 points over two weeks. No adverse events were observed.

CONCLUSIONS: AVP (4-9) fragments may influence cognitive processes and glymphatic-related pathways. These findings should be interpreted cautiously given the small sample size and open-label design but may provide a basis for future controlled investigations.},
}

@article {pmid42877345,
year = {2026},
author = {Xin, J and Zhang, H and Cai, S and Li, J and Dou, G and Estrada, BB and Walker, C and Storm, R and Chen, X},
title = {Diagnostic journey, biomarker testing, treatment, and care partner burden in patients with mild cognitive impairment and Alzheimer's disease dementia in China: A real-world survey.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261447853},
pmid = {42877345},
issn = {2542-4823},
abstract = {BACKGROUND: The prevalence of Alzheimer's disease (AD) is rising in China. Although disease-modifying treatments are available, their efficacy is mostly seen in the early stage. Timely and accurate diagnosis is crucial for AD management.

OBJECTIVE: This study aimed to describe the diagnostic trajectory, current treatments, and care burden for mild cognitive impairment (MCI)/AD in China.

METHODS: Data were derived from the Adelphi Real World Dementia Disease Specific Programme™, a cross-sectional survey of neurologists, patients with MCI/AD dementia and their care partners, conducted in China from February-May 2024. Patient characteristics, diagnoses, treatments, and care were reported by neurologists and supplemented by self-reports from patients and care partners.

RESULTS: Overall, 93 neurologists reported on 774 patients. Of patients with a Mini-Mental State Examination (MMSE) score at the time of survey (n = 699), mean (standard deviation) age was 69.3 (8.2) years, 49.6% (n = 347) female and most had MCI/mild AD (MMSE 20-28) at survey (52.5%, n = 367). Over one-third of patients presented with moderate to severe disease at initial consultation (34.7%, n = 203) and at diagnosis (36.2%, n = 265). Biomarker testing was infrequently used in diagnosis, with cerebrospinal fluid being the most used (11.2%, n = 81) and physician-reported challenges including cost, patient reluctance, and availability. Most patients received only non-professional care primarily from a partner/spouse and/or children, who spent up to 47.0 (45.8) hours per week caring.

CONCLUSIONS: Challenges in early and biomarker-based diagnosis were identified and care partners continued to experience a substantial burden. Continued efforts are needed to ensure the healthcare system's preparedness for the AD epidemic.},
}

@article {pmid42863362,
year = {2026},
author = {Zhou, Z},
title = {Uncovering the mechanism of gastrodin in treating Alzheimer's disease through bioinformatics, machine learning, and virtual gene knockout technology.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 2},
pages = {109464},
doi = {10.1016/j.compbiolchem.2026.109464},
pmid = {42863362},
issn = {1476-928X},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Gastrodin is a natural compound with neuroprotective activity; however, the precise molecular mechanisms underlying its therapeutic effects on human AD remain unclear. This study employed bioinformatics approaches to systematically elucidate the therapeutic mechanisms of gastrodin in AD. Pharmacokinetic analysis showed that gastrodin exhibited favorable drug-like properties (bioavailability score: 0.55; LogP: -0.85) and an acceptable overall toxicity profile, although predicted nephrotoxicity (0.71) and ototoxicity (0.908) scores suggest potential safety concerns warranting further investigation. Next, differentially expressed genes (DEGs) associated with AD were screened from GEO datasets, yielding 13 core targets that overlapped with gastrodin-responsive genes. Functional enrichment analysis indicated significant enrichment of these targets in signaling pathways closely related to neuroinflammation and cell survival, including the Ras-proximate 1 (Rap1), Ras, mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) pathways. The Ridge model achieved AUCs of 0.898 in the training set and 0.859 in the GSE37263 cohort, but showed modest generalizability in the GSE138260 cohort (AUC = 0.684), highlighting the heterogeneity of external datasets. Further single-cell transcriptomic analysis revealed specific upregulation of insulin-like growth factor 1 receptor (IGF1R) in brain endothelial cells of AD patients. Virtual gene knockout simulations demonstrated that IGF1R knockout substantially disrupted core networks associated with endothelial functions and neurovascular homeostasis, including focal adhesion and calcium signaling pathways. Finally, molecular docking and molecular dynamics (MD) simulations revealed stable binding conformations of gastrodin to EGFR and MET, while the gastrodin-IGF1R complex exhibited a more dynamic binding behavior with conformational flexibility, suggesting an induced-fit binding mechanism. MM/PBSA calculations revealed favorable enthalpic contributions (ΔH = -17.43, -13.63, and -10.41 kcal/mol for EGFR, IGF1R, and MET, respectively) for gastrodin-target binding. In conclusion, this study suggests that gastrodin exerts multi-target effects via coordinated regulation of multiple signaling pathways. Notably, gastrodin targets IGF1R in brain endothelial cells, modulating focal adhesion/calcium signaling networks, thus providing a novel mechanistic hypothesis for AD treatment by restoring neurovascular unit homeostasis.},
}

@article {pmid42863691,
year = {2026},
author = {Urano, Y and Maeda, W and Noguchi, N},
title = {Inhibition of glycan sialylation reduces amyloid-β secretion via suppression of amyloid-β exocytosis.},
journal = {Biochimie},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biochi.2026.10.016},
pmid = {42863691},
issn = {1638-6183},
abstract = {Among nutrient-sensitive regulatory mechanisms, protein glycosylation is a key post-translational modification that links metabolism to protein function. Amyloid-β (Aβ) peptides play a crucial role in the pathogenesis of Alzheimer's disease (AD). Because excessive accumulation of Aβ is believed to drive AD progression, approaches that reduce Aβ production and secretion remain of considerable therapeutic interest. Accumulating evidence suggests that protein glycosylation influences the processing and trafficking of amyloid-β precursor protein (APP) and other proteins involved in Aβ metabolism. However, while N-linked protein glycosylation has been shown to affect Aβ production, the specific contribution of protein terminal glycan sialylation remains incompletely understood. In this study, we investigated the effects of inhibiting glycan sialylation on Aβ production using CHO cells stably expressing human APP. Treatment with the sialyltransferase inhibitor P-3Fax-Neu5Ac (P-3Fax) significantly reduced extracellular Aβ levels, while intracellular Aβ levels were increased. Importantly, P-3Fax treatment did not alter β-secretase- or γ-secretase-mediated cleavage of their substrates, indicating that changes in secretase activity do not account for the reduction in extracellular Aβ. In addition, P-3Fax treatment markedly reduced plasma membrane levels of lysosome-associated membrane protein 1 (LAMP1), consistent with impaired lysosomal exocytosis. Taken together, these results indicate that inhibition of sialylation by P-3Fax reduces extracellular Aβ levels independently of secretase activity, potentially through impaired lysosomal exocytotic pathways. Our findings identify glycan sialylation as a key regulatory factor in Aβ trafficking and provide new insight into the cellular mechanisms controlling Aβ homeostasis.},
}

@article {pmid42863694,
year = {2026},
author = {Tanahashi, M and Kozuka, A and Sasakawa, N and Niikura, T},
title = {Humanin attenuates neuronal cellular senescence and preserves neurotransmitter release in differentiated PC12 cells.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.10.017},
pmid = {42863694},
issn = {1873-7544},
abstract = {Cellular senescence, characterized as a permanent arrest of cell proliferation, is triggered by various types of stress. Senescent cells are identified by markers, including senescence-associated β-galactosidase (SA-β-gal) activity and the secretion of senescence-associated secretory phenotype (SASP) factors. These senescent phenotypes have been observed in neurons, suggesting that cellular senescence may contribute to the pathogenesis of neurodegenerative diseases. Humanin (HN), an endogenous short peptide, mitigates Alzheimer's disease-associated pathologies, including amyloid β-induced neuronal cell death. Overexpression of HN extends the lifespan of nematodes, suggesting a potential anti-aging role for this peptide. Here, we first investigated the effect of HN on cellular senescence in mouse primary cortical neurons. Chronic treatment with HNG, a highly potent HN derivative, attenuated prolonged culture-induced senescence. To further determine whether this anti-senescent effect is associated with preserved exocytotic function, we employed a glutamate-induced senescence model in neuronal-differentiated PC12 cells. In this system, HNG mitigated changes in senescence-associated markers, including increases in SA-β-gal activity, Ki67 expression, and SASP factor expression. In addition, acetylcholine-induced dopamine release was reduced in senescent PC12 cells, whereas chronic HN treatment sustained the expression levels of synapsin 1 and synaptophysin and attenuated the senescence-associated decrease in neurotransmitter release. These findings suggest that HN suppresses senescence and sustains exocytosis activity in neuronal cells, supporting an anti-aging function of HN at the cellular level.},
}

@article {pmid42863728,
year = {2026},
author = {Li, Y and Tang, ZL and Liu, FW and Chen, M and Chang, SQ and Ding, FM and Bian, QL and Pan, JP and Qiu, ZC and Kong, MW and Li, Y and Chen, JX},
title = {Si-Shen-San Attenuates Alzheimer's Disease Pathology and Cognitive Deficits Through Multi-Target Regulation of Astrocyte Function and Synaptic Plasticity.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122475},
doi = {10.1016/j.jep.2026.122475},
pmid = {42863728},
issn = {1872-7573},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by cognitive decline, amyloid-β (Aβ) deposition, tau hyperphosphorylation, synaptic dysfunction, and astrocyte dysregulation. The constituent herbs of the traditional Chinese medicine formula Si-Shen-San (SSS) have been used to ameliorate cognitive impairment. However, the comprehensive chemical profile, core bioactive constituents, and underlying mechanisms of action of SSS remain to be fully elucidated.

AIM OF THE STUDY: This study aims to systematically investigate the therapeutic potential of SSS against AD and to clarify its multi-faceted mechanisms of action, with a focus on astrocyte-mediated neuroprotection, synaptic repair, and modulation of core AD pathologies.

MATERIALS AND METHODS: Ultra-high performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UHPLC-Q/TOF-MS) was used to characterize the chemical constituents of SSS extract and SSS-containing serum. In vivo, 3×Tg-AD mice were orally administered SSS. And cognitive function, AD-related pathology, synaptic integrity, and astrocyte-associated molecular changes were evaluated using behavioral, histological, biochemical, ultrastructural, and electrophysiological approaches. In vitro, an astrocyte-conditioned medium paradigm was used to examine whether SSS-induced changes in astrocytes were associated with protection of HT22 neurons against glutamate-induced injury.

RESULTS: UHPLC-Q/TOF-MS tentatively annotated 525 and 318 compounds in the SSS extract and drug-containing serum. In 3×Tg-AD mice, SSS improved cognitive performance, reduced hippocampal 6E10- and ThS-positive Aβ-like immunoreactivity and tau phosphorylation at Thr231 and Ser404, and preserved synaptic structure and function. The reduction in tau phosphorylation was accompanied by changes in GSK-3β signaling. SSS treatment was also associated with reduced astrocyte reactivity, increased GLT-1 expression, and restoration of astrocyte-associated homeostatic markers. In vitro, conditioned medium derived from SSS-treated C8-D1A astrocytes alleviated glutamate-induced injury in HT22 neurons and was accompanied by activation of neuronal CREB-BDNF signaling.

CONCLUSION: SSS ameliorated cognitive deficits and multiple AD-related pathological alterations in 3×Tg-AD mice. These effects were associated with restoration of astrocyte-related homeostatic features, improved glutamate regulation, preservation of synaptic integrity, and activation of CREB-BDNF signaling. These findings provide an experimental foundation for SSS as a potential therapeutic strategy for AD and highlight astrocyte homeostasis as a promising target for future drug development.},
}

@article {pmid42865133,
year = {2026},
author = {Lv, Y and Shi, M and Zhao, Y and Yu, Y and Lv, J and Zhao, H},
title = {Context-dependent TREM2 signalling in myeloid cells: Molecular mechanisms and immunotherapeutic divergence in neurodegeneration and cancer.},
journal = {Clinical and translational medicine},
volume = {16},
number = {10},
pages = {e70863},
pmid = {42865133},
issn = {2001-1326},
support = {ZR2022QH372//Shandong Province Natural Science Foundation/ ; },
mesh = {Humans ; *Receptors, Immunologic/metabolism ; *Membrane Glycoproteins/metabolism ; *Signal Transduction ; *Myeloid Cells/metabolism/immunology ; *Neoplasms/therapy/immunology ; Animals ; *Immunotherapy/methods ; *Neurodegenerative Diseases/therapy/immunology ; },
abstract = {BACKGROUND: Triggering receptor expressed on myeloid cells 2 (TREM2) is a pivotal lipid-sensing receptor that governs the functional plasticity and metabolic fitness of mononuclear phagocytes, including microglia, osteoclasts, dendritic cells and tissue-resident macrophages. While originally identified as a genetic risk factor for Alzheimer's disease (AD), TREM2 functions as a context-dependent immunometabolic checkpoint rather than a uniform phenotypic driver, exerting divergent biological outputs dictated by distinct tissue microenvironments and ligand repertoires.

SUMMARY OF KEY CONTENTS: This review provides a comprehensive synthesis of TREM2 immunobiology, detailing how ligand engagement-including cell-surface phospholipids and apolipoprotein E (ApoE)-activates the DAP12/DAP10-SYK-PI3K-mTOR signalling axis. This coordinated intracellular cascade instructively drives myeloid adaptation towards metabolically competent disease-associated microglia (DAM) and lipid-associated macrophage (LAM) states, sustaining bioenergetics and debris clearance under pathological stress. Across neurodegenerative proteinopathies and acute cerebral ischemia, TREM2 signalling is predominantly neuroprotective by promoting aggregate compaction and mitigating secondary excitotoxicity, although chronic dysregulated activation may drive stage-dependent neuroinflammation. In peripheral inflammatory pathologies such as rheumatoid arthritis and sepsis, TREM2 fine-tunes macrophage efferocytosis and systemic metabolic thresholds. In oncology, TREM2 displays a complex, microenvironment-dependent divergence: in central nervous system malignancies such as glioblastoma (GBM), TREM2 exerts controversial, stage-dependent effects, spanning microglial tumour containment in early stages versus pro-tumoural myelin recycling and immunosuppression by monocyte-derived macrophages in post-treatment recurrence; conversely, in peripheral solid tumours, monocyte-derived TREM2+ tumour-associated macrophages (TAMs) predominantly orchestrate an immunosuppressive, nutrient-deprived niche that impairs cytotoxic T-cell function. Furthermore, we synthesise emerging paradigms along the bidirectional microbiome-gut-brain-tumour axis, elucidating how commensal and intra-tumoural microbial cues dynamically calibrate myeloid signalling tone and therapeutic susceptibility.

CONCLUSION: We address translation bottlenecks-including blood-brain barrier (BBB) shuttles, human trial scarcity and soluble TREM2 (sTREM2) biomarker harmonisation-outlining a biomarker-guided, context-tailored precision therapeutic framework for targeting the TREM2 axis.},
}

Humans
*Receptors, Immunologic/metabolism
*Membrane Glycoproteins/metabolism
*Signal Transduction
*Myeloid Cells/metabolism/immunology
*Neoplasms/therapy/immunology
Animals
*Immunotherapy/methods
*Neurodegenerative Diseases/therapy/immunology

@article {pmid42865340,
year = {2026},
author = {Kamonnat, C and Thongdechsri, S and Kraokaew, P and Niamnont, N and Sobhon, P and Meemon, K},
title = {Protective Role of Holothuria leucospilota Extract Against Amyloid-β Toxicity via Autophagy and Antioxidant Mechanisms in Caenorhabditis elegans Model.},
journal = {Oxidative medicine and cellular longevity},
volume = {2026},
number = {1},
pages = {e1471919},
pmid = {42865340},
issn = {1942-0994},
support = {//National Research Council of Thailand/ ; N42A660511//Mahidol University/ ; AN-KME-3-66-02//Central Instrument Facility (CIF)/ ; },
mesh = {Animals ; *Caenorhabditis elegans/drug effects/metabolism ; *Amyloid beta-Peptides/toxicity/metabolism ; *Autophagy/drug effects ; *Antioxidants/pharmacology ; *Holothuria/chemistry ; Oxidative Stress/drug effects ; Disease Models, Animal ; Reactive Oxygen Species/metabolism ; *Plant Extracts/pharmacology ; Caenorhabditis elegans Proteins/metabolism ; Alzheimer Disease/drug therapy ; Animals, Genetically Modified ; },
abstract = {Alzheimer's disease (AD) is a major global health challenge characterized by cognitive decline and neuronal degeneration driven by amyloid-β (Aβ) aggregation and oxidative stress. Given the limited efficacy and adverse effects of current pharmacological therapies, food-derived bioactive compounds have gained increasing attention as potential preventive strategies against neurodegenerative disorders. In this study, we investigated the neuroprotective effects of Holothuria leucospilota extracts using a transgenic Caenorhabditis elegans model of AD. Our results demonstrated that H. leucospilota hexane extract (HLHE) at 500 µg/mL significantly delayed Aβ-induced paralysis and improved chemotaxis behavior. Consistently, HLHE treatment reduced Aβ deposition and decreased both high- and low-molecular weights of Aβ oligomers, as determined by automated Western blot analysis. Additionally, HLHE also reduced reactive oxygen species (ROS) levels. Transcriptomic and RT-qPCR analyses revealed that HLHE enhanced autophagic activity through the upregulation of bec-1 (autophagy initiation) and lysosomal genes (cpr-1, cpr-2, and cpr-5). Furthermore, HLHE activated antioxidant defense pathways via the insulin/IGF-1 signaling (IIS) axis, specifically upregulating genes associated with SKN-1 pathway (pmk-1, skn-1, gst-4, and gst-10) and HSF-1 pathway (hsf-1, hsp-16.1, hsp-12.6, and mtl-1). HLHE also promoted nuclear localization of SKN-1 and increased expression of its downstream target gst-4. Chemical analysis revealed that HLHE contained arachidonic acid (21.12%) and other bioactive lipid compounds as major constituents, suggesting a synergistic role in promoting autophagy and antioxidant responses. Collectively, this study suggests that HLHE confers neuroprotection against Aβ-induced toxicity by activating autophagy and oxidative stress defense mechanisms, supporting its potential development as a food-derived preventive or therapeutic agent for AD.},
}

Animals
*Caenorhabditis elegans/drug effects/metabolism
*Amyloid beta-Peptides/toxicity/metabolism
*Autophagy/drug effects
*Antioxidants/pharmacology
*Holothuria/chemistry
Oxidative Stress/drug effects
Disease Models, Animal
Reactive Oxygen Species/metabolism
*Plant Extracts/pharmacology
Caenorhabditis elegans Proteins/metabolism
Alzheimer Disease/drug therapy
Animals, Genetically Modified

@article {pmid42865480,
year = {2026},
author = {Li, SY and Zhang, JX and Huang, LZ and Wu, HB and Ye, YB and Liu, A and Chen, J and Lai, S},
title = {Efficacy and safety of lecanemab monoclonal antibody in the treatment of mild to moderate Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1947129},
pmid = {42865480},
issn = {1663-9812},
abstract = {BACKGROUND: Lecanemab is a novel therapy for Alzheimer's disease (AD), but comprehensive evidence is lacking. This systematic review and meta-analysis evaluated the efficacy and safety in AD.

METHODS: Registered in PROSPERO (CRD420251146867). PubMed, Embase, Cochrane Library, Web of Science, and Scopus were searched for English-language RCTs. Efficacy and safety were evaluated using the risk difference with a Mantel-Haenszel fixed-effects model. Study quality and sensitivity were assessed using Cochrane risk-of-bias and leave-one-out methods. Primary outcomes: mean changes in Alzheimer's Disease Composite Score (ADCOMS), Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and amyloid burden on positron emission tomography (PET). Secondary: adverse events including amyloid-related imaging abnormalities with edema (ARIA-E), ARIA with hemorrhage (ARIA-H), death, treatment-emergent adverse events (TEAEs), headache, dizziness, and urinary tract infection.

RESULTS: A total of five articles involving 8 clinical trials were included. Based on the fixed-effect model, lecanemab treatment significantly improved cognitive performance on ADCOMS (SMD -0.1999, 95% CI [-0.2831, -0.1167], I[2] = 0%, P < 0.00001), CDR-SB (SMD -0.1853, 95% CI [-0.2683, -0.1024], I[2] = 0%, P < 0.0001), ADAS-Cog (SMD -0.1821, 95% CI [-0.2670, -0.0973], I[2] = 0%, P < 0.0001) and amyloid burden on PET (SMD -1.1872, 95% CI [-2.2474, -0.1270], I[2] = 96%, P = 0.03). Sensitivity analysis indicated stability. However, lecanemab was associated with an increased risk of TEAEs (MH RR 1.0730, 95% Cl [1.0296, 1.1183], I[2] = 0%, P = 0.0008) and an increased risk of headache (MH RR 1.3617, 95% Cl [1.0243, 1.8103], I[2] = 0%, P = 0.03). Sensitivity analysis indicated that both results were stable. The lecanemab group showed no significant differences in the risks of death, dizziness, or urinary tract infection compared with the control group. In addition, the lecanemab group showed a significantly increased risk of ARIA-E (MH RR 5.9948, 95% CI [3.9047, 9.2037], I[2] = 86%, P < 0.00001) and ARIA-H (MH RR 1.7490, 95% CI [1.3896, 2.2014], I[2] = 41%, P < 0.00001). Sensitivity analyses confirmed the stability of the TEAE finding, while the headache result should be interpreted with caution due to the limited number of studies. After excluding Honig et al. (OLE) 2021 via leave-one-out, results became stable, likely due to its open-label design.

CONCLUSION: Lecanemab slowed cognitive decline versus placebo in mild-to-moderate AD by ADCOMS, CDR-SB, and ADAS-Cog. High heterogeneity in PET amyloid burden warrants future RCTs. Nevertheless, lecanemab was associated with an increased risk of TEAEs and headache.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251146867.},
}

@article {pmid42865621,
year = {2026},
author = {Tan, W and Han, X and Wang, X and Tang, M and Li, S and Liu, H and Zhang, J and Wang, J and Liu, G},
title = {Multimodal MRI to elucidate cross-organ coupling mechanisms of the heart-brain axis.},
journal = {Frontiers in cardiovascular medicine},
volume = {13},
number = {},
pages = {1914265},
pmid = {42865621},
issn = {2297-055X},
abstract = {Cardiovascular and cerebrovascular diseases (CCVDs) are leading causes of mortality and disability worldwide, and their development is closely linked to bidirectional interactions between the heart and the brain. The heart-brain axis, a systemic framework that integrates neural, humoral, and inflammatory pathways, provides an important theoretical basis for understanding heart-brain comorbidities. With continuous advances in magnetic resonance imaging(MRI), research in this field has progressively shifted from the traditional single-organ diagnostic model to cross-organ and system-oriented strategies for prevention and management. Centered on cardiac magnetic resonance (CMR) and brain MRI, and complemented by quantitative, diffusion, functional, ultra-high-field, and metabolic imaging techniques, multimodal MRI has become a powerful tool for comprehensively characterizing myocardial remodeling, alterations in brain networks, and their coupling relationships. These techniques have been widely applied in studies of representative heart-brain comorbidities, including cardiac dysfunction associated with acute brain injury, cognitive impairment related to heart failure, and cardiovascular abnormalities associated with neurodegenerative diseases, such as Alzheimer's disease (AD). Such studies have not only revealed structural and functional alterations in the heart and brain but have also provided important insights into potential mechanisms, including autonomic imbalance, neuroendocrine activation, and inflammatory responses. However, current heart-brain axis research remains largely based on correlational analyses, whereas causal inference and characterization of dynamic mechanisms remain insufficient. In addition, significant challenges persist in multimodal data integration and clinical translation. Overall, MRI is driving heart-brain axis research from structural characterization toward mechanistic investigation. In the future, integrating imaging, physiological, and genetic information may enable early identification, risk stratification, and precision intervention for heart-brain comorbidities, thereby promoting a transition in medical practice from single-organ management to systemic prevention and treatment.},
}

@article {pmid42865677,
year = {2026},
author = {Wahbeh, H and Cooley, S and Chamberlin, SR and Brophy, T and Hameroff, S},
title = {Home-administered unfocused transcranial ultrasound in subjective cognitive decline and dementia: an open-label, uncontrolled feasibility pilot study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1937897},
pmid = {42865677},
issn = {1663-4365},
abstract = {BACKGROUND: Memory and cognitive impairments remain disabling, with few effective treatments. Low-intensity transcranial ultrasound (TUS) is a non-invasive neuromodulation approach with a favorable safety profile and preliminary evidence of cognitive benefit, with one hypothesized but unproven mechanism involving microtubule resonance and reassembly.

OBJECTIVES: This open-label pilot study evaluated the safety and preliminary efficacy of the US Pro2000 unfocused ultrasound device in adults with memory or cognitive difficulties, a sample spanning subjective cognitive decline among self-administering participants to diagnosed dementia among caregiver-rated recipients, and described self-reported symptom trajectories.

METHODS: In a within-participant design, adults with self-reported cognitive impairment, or their caregivers, applied the device at the right temporal window for 5 min three times daily (target 15 min/day), in cycles of 3 weeks on and 1 week off. Outcomes (GAD-7, CESD-5, Inoue battery, and caregiver-rated MDS 3.0) and adverse events were collected online. Mixed-effects models with age and device-use covariates assessed change over time, with False Discovery Rate correction within aim.

RESULTS: Twenty-seven participants enrolled and 26 initiated treatment. Across 2,174 daily assessments, no serious or unanticipated adverse events occurred; only headache (15.4%) and transient jaw clenching (3.8%) were possibly related, and none caused discontinuation. Among self-administered participants, depression (CESD-5) declined significantly (p_FDR = 0.016) and five of eight monthly self-report symptoms improved, including memory, word-finding, and problem-solving (all p_FDR ≤ 0.040); anxiety trended downward, and the objective cognitive battery, near ceiling at baseline, did not change. Caregiver-rated outcomes were stable. Device use showed no dose response, and sensitivity analyses were consistent.

CONCLUSION: Home-based self-administered low-intensity TUS was well tolerated, with only mild transient events, although adverse-event ascertainment relied on unblinded self-report and relatedness judgments were made by unblinded investigators. Efficacy signals were confined to self-report, while objective cognition and caregiver ratings were unchanged. The uncontrolled design, small subgroups, and reliance on self-report preclude causal inference. These findings support the safety and feasibility of TUS and justify an adequately powered, double-blind, sham-controlled trial.},
}

@article {pmid42865929,
year = {2026},
author = {Ponomareva, EV and Selezneva, ND and Boksha, IS and Savushkina, OK and Prokhorova, TA and Tereshkina, EB and Zozulya, SA and Gavrilova, SI and Kolykhalov, IV},
title = {Pilot clinical study of Taxifolin Aqua effect in patients with amnestic mild cognitive impairment.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1814042},
pmid = {42865929},
issn = {1664-0640},
abstract = {Taxifolin (dihydroquercetin), a potent antioxidant flavonoid, shows promise for neurodegenerative conditions. Our pilot study aimed at evaluation the efficacy and safety of Taxifolin in patients with amnestic mild cognitive impairment (aMCI) and monitored a set of blood measures. Twenty-three patients (18 female; aged 53-87) received dihydroquercetin oral solution for 8 weeks with a 4-week follow-up period in an open-label study design. Thirteen patients with aMCI were monitored as controls. Outcomes were assessed using cognitive status (MMSE, MoCA, FCSRT-IR), neuropsychiatric symptoms' (NPI-Q, HDRS), and rater's impression (CGI) scales, along with blood measures monitoring (glutathione reductase (GR), glutamate dehydrogenase (GDH), and superoxide dismutase (SOD); plasma neutrophil elastase (NE), alpha-1-proteinase inhibitor (alpha-1PI)). Responder classification using composite Z-score changes was based on all clinical scales. Results: Eleven patients were classified as responders, showing significant MMSE and MoCA improvement (mean +2.73 points, p=0.001) sustained through 4-week follow-up. Non-responders and control group showed slight cognitive decline. Composite Z-score changes at the 4-week follow-up revealed differences between responders/non-responders (ANOVA F(2,20)=17.38, p=0.001); biomarker analysis revealed difference in NE/alpha-1PI ratio (p=0.034), SOD (p=0.023), and GR dynamics (p=0.022), which correlated negatively with clinical response (R=-0.547, p=0.007), and baseline GDH (p=0.049). Conclusion: Taxifolin treatment resulted in significant cognitive benefits in ~half of aMCI patients, with effects sustained for one month post-treatment. Biomarker changes reveal possible mechanisms involving oxidative stress modulation and inflammatory pathways. These findings support further controlled trials of Taxifolin in populations at risk of Alzheimer's disease.},
}

@article {pmid42866370,
year = {2026},
author = {Wang, T and Wang, L and Cao, J and Zhao, Y and He, Z and Lu, F},
title = {Remodeling of the brain immune microenvironment in Alzheimer's disease: interactions among microglia, astrocytes, complement, and the neurovascular unit.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1956600},
pmid = {42866370},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/pathology/metabolism ; *Microglia/immunology/metabolism/pathology ; *Astrocytes/immunology/metabolism/pathology ; *Complement System Proteins/immunology/metabolism ; *Brain/immunology/pathology/metabolism/blood supply ; Animals ; *Cellular Microenvironment/immunology ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease is defined by amyloid-β deposition and tau pathology, yet comparable pathological burdens do not necessarily correspond to similar cognitive trajectories, regional patterns of injury, or treatment responses. This discordance suggests that the cellular and tissue microenvironment may materially shape disease progression. Genetic studies, single-cell and spatial omics, and human-derived models further indicate that microglia, astrocytes, the complement system, and the neurovascular unit undergo coordinated remodeling during the preclinical phase of AD and influence pathological spread, synaptic injury, and neurodegeneration through intercellular interactions. Remodeling of the brain immune microenvironment is regionally specific, stage dependent, and heterogeneous across cellular states; conventional pro-inflammatory/anti-inflammatory or activated/resting dichotomies therefore fail to capture its dynamics. This review examines the remodeling of the AD brain immune microenvironment through interactions among microglia, astrocytes, complement, and the neurovascular unit, with emphasis on their roles in Aβ and tau pathology, synaptic injury, lipid homeostasis, and vascular dysfunction, and considers the interpretive limits of single-cell and spatial-omics evidence. Current evidence supports a dynamically reconfigured system rather than a uniformly escalating inflammatory response. Therapeutic strategies should move beyond broad anti-inflammatory approaches to preserve effective pathological clearance within appropriate disease windows, limit maladaptive synaptic injury, and restore glial and neurovascular homeostasis.},
}

Humans
*Alzheimer Disease/immunology/pathology/metabolism
*Microglia/immunology/metabolism/pathology
*Astrocytes/immunology/metabolism/pathology
*Complement System Proteins/immunology/metabolism
*Brain/immunology/pathology/metabolism/blood supply
Animals
*Cellular Microenvironment/immunology
Amyloid beta-Peptides/metabolism

@article {pmid42866775,
year = {2026},
author = {Bhatia, V and Khatak, A},
title = {A positive Alzheimer's blood biomarker is not a diagnosis: the presence-primacy-permission framework for plasma p-tau217.},
journal = {Annals of medicine and surgery (2012)},
volume = {88},
number = {10},
pages = {6232-6234},
pmid = {42866775},
issn = {2049-0801},
abstract = {Validated plasma phosphorylated tau 217 (p-tau217) assays identify Alzheimer disease pathology with high accuracy. Wider clinical use creates a risk of postanalytic misclassification when pathology is converted directly into a clinical diagnosis or treatment decision. This editorial examines why accuracy relative to amyloid positron emission tomography or cerebrospinal fluid biomarkers does not establish that Alzheimer disease is the principal cause of a patient's cognitive syndrome. It describes three substitutions: pathology for diagnosis, presence for primacy, and diagnosis for treatment eligibility. We propose the presence-primacy-permission framework to distinguish confirmation of pathology from clinical-biological concordance and treatment suitability. Presence requires appropriate patient selection, a validated assay, and context-specific interpretation. Primacy requires integration of cognitive phenotype, trajectory, functional status, neurologic examination, structural imaging, and coexisting pathology. Permission requires assessment of clinical stage, hemorrhagic risk, treatment feasibility, and patient goals. Separate documentation of the biomarker result, syndrome, etiologic attribution, and actionability may reduce premature diagnostic closure while preserving the clinical value of p-tau217.},
}

@article {pmid42867612,
year = {2026},
author = {Fang, X and Border, JJ and Zhang, H and Morgan, GC and Gregory, A and Hanscom-Trofy, Y and Dong, R and Yang, J and Hwang, SH and Morisseau, C and Hammock, BD and Fan, F and Roman, RJ},
title = {Inhibition of soluble epoxide hydrolase rescues cognitive deficits by preserving neurovascular integrity and attenuating glial and neuropathology in diabetic-related dementia.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42867612},
issn = {2509-2723},
support = {AG079336//NIH/ ; AG057842/AG/NIA NIH HHS/United States ; AG094068/AG/NIA NIH HHS/United States ; R35ES030443/ES/NIEHS NIH HHS/United States ; U54NS127758/NS/NINDS NIH HHS/United States ; A25-1690//Harrington Discovery Institute, University Hospitals/ ; 25PRE1365157//American Heart Association/ ; 25POST1363814//American Heart Association/ ; TRIBA/ Physiology Faculty Startup Fund//Augusta University/ ; },
abstract = {Diabetes mellitus (DM) is a major risk factor contributing to the development of Alzheimer's disease-related dementias (ADRD). While one of the early symptoms of both Alzheimer's disease (AD) and DM-related ADRD is a reduction in cerebral blood flow, the underlying biological mechanisms driving this decline remain to be fully elucidated. Genome-wide association studies have linked AD/ADRD to single-nucleotide polymorphisms in the gene encoding soluble epoxide hydrolase (sEH), an enzyme we previously reported to be upregulated in the brains of an AD rat model. Our previous studies also demonstrated that chronic sEH inhibition with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) preserves hippocampal-dependent spatial learning and memory and improves cerebral hemodynamics in both AD and DM-ADRD models. In the present study, we found that chronic TPPU treatment (1 mg/kg/day) reduced sEH expression in the brain, improved cortical-based non-spatial recognition memory involving both cortical and hippocampal networks, and reduced anxiety in DM-ADRD rats. TPPU improved brain perfusion and normalized impaired whisker-evoked functional hyperemia, an effect associated with increased Kir2.1 expression and neurovascular coupling in cerebral capillaries. Furthermore, TPPU increased tight junction protein expression (ZO-1 and OCLN), mitigated capillary rarefaction, and suppressed astrocyte and microglial activation in DM-ADRD rats. At the cellular level, TPPU attenuated hippocampal neurodegeneration, restored the expression of synaptic proteins (PSD95 and SY38), and reduced levels of proinflammatory chemokines, including MCP-1, RANTES, and MIP-1α, in the hippocampus of DM-ADRD rats. In conclusion, TPPU preserves cognitive function in DM-ADRD by mitigating cerebrovascular dysfunction, neuroinflammation and gliosis, thereby preserving synaptic integrity and neuronal survival, and represents a promising therapeutic strategy for DM-ADRD.},
}

@article {pmid42868046,
year = {2026},
author = {Lv, C and Luo, Q and Jin, F and Shao, Q and Qiu, Y and Ni, J and Liu, J and Qing, H and Quan, Z},
title = {Intermittent hypoxia training alleviates cerebral hypoperfusion and amyloid-β deposition in a mixed dementia model established by bilateral common carotid artery stenosis in early-stage 5xFAD mice.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261497235},
doi = {10.1177/13872877261497235},
pmid = {42868046},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is the most common form of dementia and often coexists with vascular pathology in clinical settings, resulting in mixed dementia with more severe symptoms and more rapid progression.ObjectiveTo investigate whether chronic cerebral hypoperfusion aggravates early AD-related pathology, we established a mixed dementia-like model by inducing bilateral common carotid artery stenosis (BCAS) in early-stage 5xFAD mice and evaluated the effects of intermittent hypoxia treatment (IHT).MethodsEarly-stage 5xFAD mice were subjected to BCAS to induce chronic cerebral hypoperfusion. Cognitive performance, cerebral perfusion, amyloid-β (Aβ) deposition, glial reactivity, tight-junction transcripts, and perivascular astrocyte-vascular organization were assessed. The therapeutic effects of IHT were then evaluated in this mixed dementia-like model.ResultsBCAS-induced hypoperfusion aggravated cognitive impairment in early-stage 5xFAD mice and accelerated pathological changes, including increased Aβ burden and stronger glial reactivity. These changes were accompanied by altered tight-junction transcripts and impaired perivascular astrocyte-vascular organization. IHT mitigated several features of the mixed dementia phenotype, including cerebral hypoperfusion, Aβ accumulation, glial reactivity, and altered perivascular AQP4/CD31 organization, while partially improving cognitive performance.ConclusionsChronic cerebral hypoperfusion can exacerbate early AD-related pathological and cognitive changes. IHT may alleviate mixed dementia-like phenotypes by improving cerebral perfusion, with accompanying changes in perivascular AQP4/CD31 organization and tight-junction transcripts.},
}

@article {pmid42869342,
year = {2026},
author = {Mikalauskaite, K and Veiveris, D and Smirnovas, V and Ziaunys, M},
title = {Effect of freeze-thaw cycle induced oligomers on alpha-synuclein liquid-liquid phase separation and aggregation.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {154845},
doi = {10.1016/j.ijbiomac.2026.154845},
pmid = {42869342},
issn = {1879-0003},
abstract = {Protein aggregation in the form of amyloid fibrils is linked with the onset and progression of several widespread and incurable disorders, including neurodegenerative Alzheimer's and Parkinson's diseases. Despite decades of research and countless attempts to discover potential aggregation-altering treatment modalities, there are still no effective cures for the majority of amyloid-related disorders. This is, in part, due to our incomplete understanding of the underlying factors that influence the phase separation and aggregation of these various disease-related proteins. Over the last few years, it has been shown that even factors such as storage conditions or sample preincubation times can affect the formation kinetics of amyloid fibrils. In the case of alpha-synuclein, even the protein purification procedure yielded different concentrations of oligomeric species, which altered the aggregation mechanism. In this work, we further explore the role of alpha-synuclein oligomers by inducing their formation via freeze-thaw cycles and analyzing their effect on liquid-liquid and liquid-solid phase transitions. Using real-time kinetic monitoring, brightfield microscopy, Fourier-transform infrared spectroscopy and atomic force microscopy, we show that the presence of freeze-thaw cycle induced alpha-synuclein oligomers has significant effects on its condensate assembly and subsequent aggregation, as well as the final structure of the formed aggregates.},
}

@article {pmid42869847,
year = {2026},
author = {Liu, X and de Boer, SCM and Tartaglia, MC and , },
title = {Sex-specific brain reserve and progression from mild cognitive impairment to Alzheimer's disease dementia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71913},
doi = {10.1002/alz.71913},
pmid = {42869847},
issn = {1552-5279},
support = {//Donald Weaver Postdoctoral Fellowship/ ; //Early Career Grant of Alzheimer Nederland/ ; //Brain Canada-Krembil/ ; //Canadian Institute of Health Research/ ; //Tanenbaum Institute of Research in Sports Science/ ; //Weston Family Foundation/ ; //Michael J. Fox Foundation for Parkinson's Research/ ; },
mesh = {Humans ; Female ; *Alzheimer Disease/pathology/diagnostic imaging/cerebrospinal fluid ; *Cognitive Dysfunction/pathology/diagnostic imaging/cerebrospinal fluid ; Male ; Disease Progression ; *Brain/pathology/diagnostic imaging ; tau Proteins/metabolism ; Aged ; Positron-Emission Tomography ; *Sex Characteristics ; Magnetic Resonance Imaging ; Atrophy ; Longitudinal Studies ; Aged, 80 and over ; Gray Matter/pathology/diagnostic imaging ; Biomarkers/cerebrospinal fluid ; },
abstract = {INTRODUCTION: Sex differences exist in Alzheimer's disease (AD) treatment response, but the role of sex in disease development and progression remains unclear.

METHODS: We performed multimodal analyses of AD biomarker-positive individuals with mild cognitive impairment (MCI) and AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI; MCI n = 593, AD n = 270) and National Alzheimer's Coordinating Center (MCI n = 436, AD n = 174). Baseline gray matter volume (GMV) was compared by sex. In ADNI, tau positron emission tomography burden and cerebrospinal fluid growth-associated protein 43 (GAP-43) were assessed. Longitudinal analyses examined atrophy and conversion from MCI to dementia.

RESULTS: Females with MCI exhibited greater baseline GMV than males primarily in the thalamus, caudate, cerebellum, postcentral gyrus, and middle cingulate gyrus, with no differences at the AD stage. Despite this, females exhibited higher baseline GAP-43, greater tau burden in temporal and parietal regions, and more rapid annual hippocampal atrophy. Conversion rates were similar.

DISCUSSION: Findings suggest that females may tolerate greater pathology at early stages but experience faster neurodegeneration later, supporting sex-specific disease trajectories and highlighting the need for sex-informed biomarkers.},
}

Humans
Female
*Alzheimer Disease/pathology/diagnostic imaging/cerebrospinal fluid
*Cognitive Dysfunction/pathology/diagnostic imaging/cerebrospinal fluid
Male
Disease Progression
*Brain/pathology/diagnostic imaging
tau Proteins/metabolism
Aged
Positron-Emission Tomography
*Sex Characteristics
Magnetic Resonance Imaging
Atrophy
Longitudinal Studies
Aged, 80 and over
Gray Matter/pathology/diagnostic imaging
Biomarkers/cerebrospinal fluid

@article {pmid42858079,
year = {2026},
author = {Yang, X and Ye, T and He, Y and Zhao, J and Wang, J and Cheng, X},
title = {Qi-Fu-Yin Attenuates Frailty by Regulating Gut Microbiota and Neuroendocrine Hormones in 5xFamilial Alzheimer's Disease Transgenic Mice.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {236},
pages = {},
doi = {10.3791/73003},
pmid = {42858079},
issn = {1940-087X},
mesh = {Animals ; *Alzheimer Disease/drug therapy/microbiology/blood/metabolism ; Mice, Transgenic ; Mice ; *Gastrointestinal Microbiome/drug effects ; *Drugs, Chinese Herbal/pharmacology/administration & dosage ; *Frailty/drug therapy/microbiology ; Female ; Male ; Disease Models, Animal ; },
abstract = {Frailty is a common and debilitating feature of Alzheimer's disease (AD), yet effective therapeutic strategies targeting both cognitive decline and physical frailty remain limited. Qi-Fu-Yin (QFY), a traditional Chinese herbal formulation, has been used to treat aging-related disorders, but its effects on frailty in AD and the underlying mechanisms are unclear. This study aimed to evaluate whether QFY alleviates frailty in 5xFamilial Alzheimer's Disease (FAD) transgenic mice and to explore the potential involvement of gut microbiota and neuroendocrine hormones. Mice were treated with QFY at low (2.8 g/kg), medium (5.6 g/kg), or high (11.2 g/kg) doses, or with donepezil as a positive control, for 194 days. Frailty-related behaviors were assessed using CatWalk gait analysis, grip strength, rotarod, nest-building, and aging scoring. Plasma hormone levels were measured, and fecal gut microbiota composition and function were analyzed by 16S rRNA sequencing and metagenomic analysis. QFY treatment significantly improved gait parameters, grip strength, motor coordination, nesting ability, and reduced aging scores in 5xFAD mice, with effects comparable to or superior to those of donepezil. QFY also restored aberrant levels of estradiol, testosterone, and corticosterone, and reshaped gut microbiota composition, particularly by increasing the abundance of Adlercreutzia, which negatively correlated with senescence and testosterone levels. Functional metagenomics revealed that QFY partially restored disease-associated microbial pathways, including those involved in carbohydrate metabolism and virulence. These findings suggest that QFY alleviates frailty in 5xFAD mice, with effects associated with concurrent modulation of gut microbiota and neuroendocrine function, though causal relationships require further validation. These findings support further investigation of QFY as a potential intervention for AD-associated frailty.},
}

Animals
*Alzheimer Disease/drug therapy/microbiology/blood/metabolism
Mice, Transgenic
Mice
*Gastrointestinal Microbiome/drug effects
*Drugs, Chinese Herbal/pharmacology/administration & dosage
*Frailty/drug therapy/microbiology
Female
Male
Disease Models, Animal

@article {pmid42858322,
year = {2026},
author = {Yang, Y and Zhang, X and Zan, X and Niu, C and Wei, X and Feng, P and Li, G and Gao, M},
title = {A Clearance-Repair-Activation Framework for Alzheimer's Disease: A Perspective and Validation Roadmap.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.1040},
pmid = {42858322},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) is a heterogeneous clinicobiological syndrome involving impaired protein clearance, neuroinflammation, synaptic and cellular injury, network dysfunction, and progressive functional decline. Amyloid-directed antibodies provide an evidence-based treatment backbone for selected patients with early symptomatic AD, but adjunctive strategies may be needed to address other disease mechanisms. This Perspective proposes a clearance-repair-activation framework for hypothesis-driven research. Clearance includes established pharmacological treatment and risk management as well as investigational drainage approaches; lymphaticovenous anastomosis (LVA) and deep cervical lymphaticovenous anastomosis (dcLVA) are considered only as research options within this broader domain. Repair includes neural stem-cell (NSC), induced pluripotent stem-cell-derived, engineered-cell, and secretome-based strategies, for which AD evidence remains predominantly preclinical. Activation encompasses invasive and non-invasive stimulation, sensory entrainment, neurofeedback, brain-computer interface (BCI) monitoring, and cognitive rehabilitation; BCI is positioned mainly as an experimental monitoring and adaptive rehabilitation platform. We define falsifiable links between clearance and repair readiness and between repair markers and activation responsiveness, consider adaptive and parallel alternatives to fixed sequencing, and integrate disease stage, heterogeneity, regulation, and combination-trial design. Informatics is limited to trial infrastructure and safety governance. The validation roadmap specifies success criteria, stop rules, interaction testing, clinically meaningful outcomes, and long-term surveillance.},
}

@article {pmid42858330,
year = {2026},
author = {Zhang, K and Zhang, Y and Jiang, X and Chen, X},
title = {Neuroimmune State Configurations at the Amyloid-Tau Interface in Alzheimer's Disease: A Testable Framework.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0888},
pmid = {42858330},
issn = {2152-5250},
abstract = {Neuroimmune mechanisms are central to Alzheimer's disease (AD), but a single continuum of "more inflammation" does not explain why similar amyloid-β (Aβ) and tau burdens are associated with different clinical trajectories, tissue responses, and treatment risks. We present a testable neuroimmune-state framework that integrates, rather than replaces, the AT(N) system, cellular-phase models, and transcriptional descriptions of disease-associated microglia and reactive astrocytes. The framework treats neuroimmune states as multidimensional, regionally heterogeneous configurations defined by pathological substrate, cellular program, biological target, vascular and aging context, and measurable patient-level readouts. We distinguish four meanings of the amyloid-tau interface: a biomarker interface, a spatial tissue interface, a cellular-state interface, and a clinical-progression interface. We then examine the hypothesis of phagocytic target switching, in which clearance pathways that support plaque compaction or debris removal may, under selected tau- and complement-rich conditions, contribute to removal of stressed but potentially functional synapses. We explicitly separate evidence from longitudinal human studies, cross-sectional biomarkers, human genetics, postmortem tissue, animal models, and in vitro systems. Current biomarkers cannot yet assign patients to validated discrete neuroimmune states; proposed state readers should therefore be probabilistic, allow regional coexistence and parallel vascular-immune trajectories, and be tested for incremental value beyond established AD biomarkers and co-pathologies. Finally, we organize immune-directed interventions by clinical evidence level and frame stage matching as a research strategy rather than a treatment algorithm. The model is useful only if its predictions can be prospectively supported or falsified.},
}

@article {pmid42858944,
year = {2026},
author = {Patel, DR and Rangasamy, SB and Gorai, S and Paidi, RK and Pahan, K},
title = {Glyceryl tribenzoate, a flavoring agent, stimulates hippocampal plasticity and protects memory via PPARα.},
journal = {Neurochemistry international},
volume = {201},
number = {},
pages = {106270},
doi = {10.1016/j.neuint.2026.106270},
pmid = {42858944},
issn = {1872-9754},
abstract = {Glyceryl tribenzoate (GTB) or tribenzoin is a flavoring agent with characteristic anti-microbial property. We have already delineated GTB's immunomodulatory role via the enrichment of regulatory T cells in mouse models of multiple sclerosis and anti-neuroinflammatory role via the reduction of glial activation in a monkey model of Parkinson's disease and a mouse model of Huntington's disease. However, its role has never been explored in Alzheimer's disease (AD), the most common neurodegenerative disorder in human. This study underlines the importance of GTB in promoting the growth and function of hippocampal neurons via upregulation of plasticity-associated genes, enrichment of dendritic spines and stimulation of inotropic calcium influx. Accordingly, oral GTB improved hippocampal plasticity and protected memory and learning in 5xFAD mice. Similarly, GTB treatment also reduced cerebral plaque load and increased the life span of aged 5xFAD mice. Interestingly, we observed that peroxisome proliferator-activated receptor alpha (PPARα), a nuclear hormone receptor, served as a receptor of GTB. Consequently, GTB was shown to improve hippocampal plasticity and increase cognitive functions in 5xFAD, but not 5xFAD/Ppara-null, mice, indicating an important role of PPARα in GTB-mediated neuroprotection. These results suggest that oral GTB may have therapeutic importance for improving hippocampal functions in AD patients.},
}

@article {pmid42859348,
year = {2026},
author = {Lin, W and Shu, Z and Liu, G and Fang, J and Ding, S},
title = {The Gut-Brain Axis and Neurodegenerative Diseases: From Mechanistic Pathways to Therapeutic Interventions.},
journal = {Probiotics and antimicrobial proteins},
volume = {},
number = {},
pages = {},
pmid = {42859348},
issn = {1867-1314},
support = {2024RC2053//Yuelushan Laboratory joint talent introduction project/ ; Grant No. kq2502176//Natural Science Foundation of Changsha, China/ ; 24B0219//Scientific Research Project of Hunan Provincial Department of Education/ ; 2025JGZD053//Hunan Province Postgraduate Education Teaching Reform Research Project/ ; 2023YFD1301200//National Key Research and Development Program of China/ ; HARS-06//Hunan Poultry Industry Technology System/ ; },
abstract = {As the global population ages, the incidence of neurodegenerative diseases (NDDs) has increased. Neurodegenerative diseases have complex pathogenesis and currently lack fundamental treatment methods. The gut-brain axis (GBA) participates in the pathogenesis of NDDs through bidirectional communication between the gut microbiota and the central nervous system (CNS). This review systematically introduces the pathogenic characteristics of representative NDDs such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), as well as the association mechanisms between these diseases and GBA. The pathogenic characteristics of NDDs are closely related to changes in the composition of the gut microbiota and differences in gut microbiota metabolites (such as short-chain fatty acids (SCFAs), neurotransmitters, tryptophan metabolites, etc.). These changes influence the CNS through multiple pathways, including neuroendocrine, vagus nerve, and immune regulation, ultimately contributing to the onset and progression of the diseases. Furthermore, we have collected and summarized preclinical and clinical evidence from recent years regarding therapeutic interventions based on the GBA mechanism, including probiotics, prebiotics, and fecal microbiota transplantation (FMT). Nevertheless, major knowledge gaps remain, particularly regarding causality between gut microbiota changes and NDDs, the underlying molecular mechanisms, and the clinical efficacy of GBA-targeted therapies. This article aims to review the mechanisms of the interaction between the gut microbiota and the brain in neurodegenerative diseases, and based on the existing experimental evidence, provide theoretical basis and future development directions for future prevention and treatment strategies targeting GBA.},
}

@article {pmid42860159,
year = {2026},
author = {Wang, M and Zhao, H and Lin, X and Ye, Z and Tu, B and Yang, Y and Wang, C and Fang, X and Fang, Q},
title = {Field-assisted interfacial passivation: Microwave-enhanced EGCG remodeling of amyloid-β42 aggregates.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {154811},
doi = {10.1016/j.ijbiomac.2026.154811},
pmid = {42860159},
issn = {1879-0003},
abstract = {Amyloid misfolding and self-assembly are central pathological events of Alzheimer's disease and related proteinopathies. Although soluble oligomers are widely considered as the primary toxic species, how therapeutic modulators alter toxicity-relevant aggregate surfaces remains poorly understood. Here, we combine cell viability assays, thioflavin T (ThT) aggregation kinetics, circular dichroism (CD), transmission electron microscopy (TEM), and atomistic molecular dynamics (MD) simulations to investigate how microwave-assisted Epigallocatechin gallate (EGCG) remodels Aβ42 aggregates. We show that microwave exposure markedly enhanced EGCG-mediated cytoprotection in BV2 microglial cells while concurrently suppressing the formation of canonical ThT-responsive amyloid species. MD simulations revealed that oscillating electric fields promote a constrained, interface-selective remodeling of protofibrillar-like aggregates rather than catastrophic depolymerization. In the initial trajectory pair, field assistance redistributed EGCG contacts across more surface residues, accompanied by reduced overall and hydrophobic protein-only solvent-accessible surface area. At a key hydrophobic interface identified by contact-occupancy analysis, the combined treatment decreased local water density and solvent accessibility, indicating reduced local hydration. We define this collective surface state- characterized by expanded EGCG coverage, reduced hydrophobic exposure, and diminished solvent accessibility - as interfacial passivation. Moreover, simulation analysis revealed that the field-assisted EGCG adsorption state remains stable for at least 500 ns after field removal, suggesting that the electric field facilitates formation of a kinetically stable surface-bound configuration. Together, these findings support field-assisted interfacial passivation as a possible mechanism for amyloid modulation and suggest that passivating toxicity-relevant aggregate surfaces, rather than achieving complete depolymerization, may represent a promising therapeutic strategy.},
}

@article {pmid42860522,
year = {2026},
author = {Shiferaw, TG and Sarkar, S and Baker, KM and Wooldridge, RS and Binfet, HM and Prozapas, VN and Ogbu, CP and Schepmoes, AA and Attah, IK and Niemeyer, CS and Sprenger, KG and Hassell, JE and Eckel, RH and Melchior, JT and Bruce, KD},
title = {ApoE lipidation state directs immunometabolic reprogramming of human microglia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71882},
pmid = {42860522},
issn = {1552-5279},
support = {R01AG079217-01/NH/NIH HHS/United States ; R01NS125591/NS/NINDS NIH HHS/United States ; T32 2T32DK120521-06//Strategic Infrastructure for Research Committee/ ; },
mesh = {Humans ; *Microglia/metabolism ; *Apolipoprotein E4/metabolism ; *Apolipoproteins E/metabolism ; *Lipid Metabolism ; Metabolic Reprogramming ; Mitochondria/metabolism ; Alzheimer Disease/metabolism ; *Apolipoprotein E3/metabolism ; Lipid Droplets/metabolism ; },
abstract = {INTRODUCTION: ApoE ε4 is the strongest genetic risk factor for Alzheimer's disease (AD). Emerging evidence suggests that ApoE4 increases AD risk by disrupting microglial metabolism and function. However, whether ApoE lipidation state contributes to microglial dysfunction remains poorly understood.

METHODS: Human microglia were treated with lipid-free (LF) or lipid-bound ApoE3 or ApoE4. Label-free, live-cell holotomography and global proteomics were used to assess isoform- and lipidation-specific effects on lipid droplet (LD) dynamics, mitochondrial morphology, and microglial phenotype.

RESULTS: ApoE4 treatment resulted in fewer but enlarged LDs and increased mitochondrial fragmentation compared to ApoE3, effects that were enhanced by lipid-bound ApoE4. Proteomic analyses revealed a strong type I interferon response in cells exposed to LF-ApoE, which was exacerbated by LF-ApoE4.

DISCUSSION: These findings indicate that lipid-bound ApoE4 drives metabolic reprogramming, whereas LF-ApoE4 promotes inflammatory signaling, identifying ApoE lipidation as a critical modifier of ApoE4-associated AD risk.},
}

Humans
*Microglia/metabolism
*Apolipoprotein E4/metabolism
*Apolipoproteins E/metabolism
*Lipid Metabolism
Metabolic Reprogramming
Mitochondria/metabolism
Alzheimer Disease/metabolism
*Apolipoprotein E3/metabolism
Lipid Droplets/metabolism

@article {pmid42861699,
year = {2026},
author = {Exalto, LG and van Alphen, JL and Barkhof, F and Teunissen, C and Vijverberg, EGB and Aarsland, D and Lemstra, AW},
title = {Dementia with Lewy bodies and amyloid pathology: Eligible for anti-amyloid treatment or not?.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71907},
pmid = {42861699},
issn = {1552-5279},
mesh = {Humans ; *Lewy Body Disease/drug therapy/pathology ; *Alzheimer Disease/drug therapy/pathology ; *Amyloid beta-Peptides/metabolism ; },
abstract = {In the future, treatment of dementia will be personalized, targeted to contributing pathologies, rather than the clinical syndrome. Anti-amyloid drugs for Alzheimer's disease are the first approved drugs; however, the impact of co‑pathology on the treatment effects remains incomplete. Currently, only patients with a clinical diagnosis of Alzheimer's disease are eligible for these new drugs, but could they also be beneficial when amyloid is present in other neurodegenerative diseases? For example, roughly 50% of patients with dementia with Lewy bodies are amyloid-positive. In this perspective, we discuss the theoretical benefits and challenges of anti-amyloid drugs in patients with a clinical diagnosis of dementia with Lewy bodies and concomitant Alzheimer's disease pathology. We show that a significant portion of newly diagnosed dementia with Lewy bodies patients could be eligible. We advocate for the systematic collection of efficacy and safety data using innovative strategies to achieve adequate statistical power.},
}

Humans
*Lewy Body Disease/drug therapy/pathology
*Alzheimer Disease/drug therapy/pathology
*Amyloid beta-Peptides/metabolism

@article {pmid42861801,
year = {2026},
author = {Alpana, and Dewangan, HK},
title = {Crossing the Blood-brain Barrier: Emerging Nanotechnological Approaches for Neurodegenerative Disease Therapy.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026454704261001071449},
pmid = {42861801},
issn = {1875-5739},
abstract = {Neurodegenerative disorders such as Parkinson's Disease (PD), Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease (HD) are characterized by progressive neuronal degeneration and severe therapeutic limitations due to the Blood-Brain Barrier (BBB). Recent advances in nanotechnology have enabled the development of nanoscale drug delivery systems capable of improving BBB penetration and enhancing therapeutic efficacy. This review discusses recent progress in Lipid Nanoparticles (LNPs), polymeric nanoparticles, exosomes, magnetic nanoparticles, gold nanoparticles, graphene quantum dots, and RNAloaded nanocarriers for brain-targeted delivery. Special emphasis is placed on receptor-mediated transcytosis, intranasal delivery, magnetic targeting, and ionizable lipid nanoparticle systems for nucleic acid delivery. Recent nanoformulations including curcumin-loaded nanoparticles, siRNA- loaded lipid nanoparticles, dopamine-loaded liposomes, and lactoferrin-functionalized polymeric nanoparticles are critically compared based on BBB penetration, therapeutic efficacy, toxicity, and translational potential. Furthermore, current clinical challenges including nanotoxicity, pharmacokinetics, large-scale manufacturing, and regulatory barriers are discussed. Nanotechnology- based therapeutics represent a promising strategy for improving diagnosis and treatment of neurodegenerative disorders and may facilitate the future development of precision nanomedicine.},
}

@article {pmid42862019,
year = {2026},
author = {Stögmann, E and Haider, L and Leinkauf, J and Nakuz, T and Untersteiner, H and Farr, C and Silvaieh, S and Parvizi, T and Wurm, R and Kasprian, G and Berger, T and Gelpi, E and Sieczkowski, EB},
title = {Progressive Amyloid-Related Imaging Abnormalities After Discontinuation of Lecanemab in Early Alzheimer Disease in an APOE ε2/ε4 Carrier.},
journal = {European journal of neurology},
volume = {33},
number = {10},
pages = {e70779},
pmid = {42862019},
issn = {1468-1331},
mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics/diagnostic imaging ; Apolipoprotein E4/genetics ; Magnetic Resonance Imaging ; Disease Progression ; *Antibodies, Monoclonal, Humanized/adverse effects ; Apolipoprotein E2/genetics ; Female ; Heterozygote ; Brain/pathology/diagnostic imaging ; Male ; },
abstract = {BACKGROUND: Amyloid-related imaging abnormalities (ARIA) are the most relevant adverse events associated with anti-amyloid therapies in Alzheimer's disease.

METHODS: We report a case of progressive ARIA after discontinuation of lecanemab in a patient with early-onset Alzheimer's disease carrying the rare APOE ε2/ε4 genotype.

RESULTS: After two infusions, mild ARIA-edema (ARIA-E) and ARIA-hemorrhage (ARIA-H) were detected on routine MRI, prompting treatment interruption. Despite partial radiologic regression, follow-up MRI 8 weeks after discontinuation demonstrated marked progression with multifocal ARIA-H displaying as superficial siderosis, while the patient remained clinically asymptomatic. Corticosteroid treatment was initiated and lecanemab permanently discontinued.

CONCLUSION: This case highlights that severe ARIA may progress beyond active treatment exposure and emphasizes the importance of continued MRI surveillance even after therapy cessation. Furthermore, the APOE ε2/ε4 genotype may represent a distinct risk factor for cerebral amyloid angiopathy-related vascular fragility and hemorrhagic ARIA.},
}

Humans
*Alzheimer Disease/drug therapy/genetics/diagnostic imaging
Apolipoprotein E4/genetics
Magnetic Resonance Imaging
Disease Progression
*Antibodies, Monoclonal, Humanized/adverse effects
Apolipoprotein E2/genetics
Female
Heterozygote
Brain/pathology/diagnostic imaging
Male

@article {pmid42862052,
year = {2026},
author = {Unnikrishnan, B and Anand, A and Fang, CN and Wu, SM and Wang, CC and Huang, CC and Chu, HW and Chang, HT},
title = {Carbon dot-based nanomaterials in neurodegeneration: addressing neurobiological barriers and targeting challenges.},
journal = {Chemical communications (Cambridge, England)},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6cc03262a},
pmid = {42862052},
issn = {1364-548X},
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, represent a major global health challenge due to their progressive nature and limited therapeutic options. One of the primary obstacles to treating these disorders is the blood-brain barrier (BBB), which restricts the delivery of most therapeutic agents into the central nervous system. In recent years, carbon-based nanomaterials, particularly carbon dot (CD) nanostructures, have emerged as promising platforms for neurological applications owing to their ultrasmall size, BBB-crossing ability, and anti-inflammatory and neuroprotective properties, in addition to tunable surface chemistry, strong photoluminescence, and favorable biocompatibility. This review provides a comprehensive overview of recent research developments in the application of CD-based nanomaterials, including carbon nanodots, carbon quantum dots, graphene quantum dots, and carbon polymer dots, for the potential treatment of neurodegenerative diseases. The synthesis strategies and carbonization approaches used to produce these carbon nanomaterials are discussed, along with their physicochemical properties relevant to neurobiological applications, such as particle size, surface functionalization, heteroatom doping, optical properties, and stability in biological environments. Furthermore, the mechanisms by which CD-based nanomaterials can traverse the BBB are examined, including receptor-mediated and adsorptive-mediated transcytosis pathways. In addition, their applications are discussed, with particular focus on their roles in bioimaging, biosensing, inhibition of pathological protein aggregation, antioxidative activity, and targeted drug delivery. Finally, key challenges related to toxicity, biodistribution, large-scale synthesis, and clinical translation are discussed, along with future perspectives for the development of multifunctional theranostic platforms. Overall, use of CD-based nanomaterials represents a promising emerging strategy for overcoming neurobiological barriers and enabling the development of next-generation nanotherapeutics for the management of neurodegenerative diseases.},
}

@article {pmid42863347,
year = {2026},
author = {Zhao, J and Qu, L and Guan, H and Che, H and Shi, F and Yang, Y},
title = {Immunosenescence as a modifiable driver of neurodegenerative diseases: Pathways and multidimensional emerging strategies for Alzheimer's and Parkinson's diseases.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {6},
pages = {e01096},
doi = {10.1016/j.neurot.2026.e01096},
pmid = {42863347},
issn = {1878-7479},
abstract = {Immunosenescence represents a core upstream driver of Alzheimer's disease (AD) and Parkinson's disease (PD), exerting its pathological effects through four mechanistically interconnected cascades: chronic inflammatory imbalance mediated by the senescence-associated secretory phenotype (SASP), oxidative stress arising from immune-metabolic reprogramming, protein homeostasis dysfunction caused by autophagy-lysosomal failure, and disrupted neuro-immune crosstalk secondary to breakdown of central nervous system (CNS) immune privilege. Current clinical practice remains largely constrained to neurotransmitter-based symptomatic management, which can neither arrest upstream pathological progression nor restore lost neuronal populations. Emerging intervention strategies targeting immunosenescence, including senolytic agents, antioxidant and metabolic modulators, autophagy restoration, and precision-targeted nanocarrier delivery, have demonstrated substantial capacity to delay disease progression in preclinical and early clinical investigations. These strategies act through selective clearance of senescent immune cells, remodeling of the neuroinflammatory microenvironment, and restoration of cellular quality-control mechanisms. The multidimensional treatment strategy approaches from the perspectives of artificial intelligence (AI) guided target discovery, nanocarrier engineering, and gut microbiota intervention to simultaneously address multiple nodes in the immunosenescence network, thereby overcoming the inherent limitations of single-target strategies. This review consolidates current mechanistic evidence and translational data to establish immunosenescence as an actionable therapeutic target and to provide a conceptual framework for precision disease-modifying therapy in AD and PD.},
}

@article {pmid42856312,
year = {2026},
author = {Mukherjee, S and Barthélemy, NR and Atri, T and Li, Y and Yen, D and He, Y and Coyle, R and Ovod, V and Franklin, EE and Xiong, C and Wang, G and Xu, J and Farsad, H and Mummery, CJ and Masters, CL and Sanchez-Valle, R and Masellis, M and Hsiung, GR and Guthier, S and Lah, JJ and Berman, SB and Roberson, ED and Surti, G and Honig, LS and Clarnette, R and Vitali, P and Ringman, J and Bird, TD and Brooks, WS and Fox, NC and Suzuki, K and Black, SE and Levin, J and Farlow, MR and Chhatwal, J and Aggarwal, NT and Jucker, M and Frosch, MP and Kofler, JK and White, C and Keene, CD and Chen, J and Glass, J and Gearing, M and Ryan, NS and Aguillón, D and Supnet-Bell, C and Gordon, BA and Benzinger, TLS and Sims, J and Yaari, R and Bittner, T and Klein, G and Delmar, P and Morris, JC and Llibre-Guerra, J and Clifford, DB and Karch, CM and McDade, E and Perrin, RJ and Bateman, RJ and , and , },
title = {Gantenerumab reduces brain amyloid-β proteoforms: Biochemical evaluation in dominantly inherited Alzheimer disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.22.26363432},
pmid = {42856312},
abstract = {UNLABELLED: Therapeutic strategies targeting amyloid-β (Aβ) in Alzheimer disease (AD) include antibodies directed against fibrillar amyloid plaques or soluble amyloid-β (Aβ) species, yet how these approaches reshape brain pathology remains poorly understood. Postmortem neuropathological assessment is crucial for evaluating the degree of Aβ removal, providing information and context that fluid biomarkers and positron emission tomography (PET) alone cannot, and guiding development of more effective disease modifying therapies for AD. In this study, using high resolution mass spectrometry we quantitatively measured Aβ and tau proteoforms in postmortem brain tissue homogenates to evaluate the impact of long-term treatment with anti-Aβ monoclonal antibodies gantenerumab or solanezumab in a clinical trial of dominantly inherited Alzheimer disease (DIAD). Symptomatic DIAD participants who had been treated for ∼ 4 years with anti-Aβ monoclonal antibodies (gantenerumab, n=4 or solanezumab, n=4) were compared with untreated, symptomatic DIAD mutation carriers (n=40) and with age-relevant non-DIAD controls with modest or no plaque pathology (n=18). Consistent with antemortem Aβ-PET findings in the clinical trial, gantenerumab-treated participant samples showed significantly lower levels of specific Aβ proteoforms (Aβ 42 , Aβ 40) in the insoluble plaque associated pool (range: 60-80 % reduction); they also showed lower levels of post-translationally modified Aβ proteoform Aβ 3pGlu in both the insoluble and soluble pool, compared to untreated DIAD participants, but without reaching the levels found in non-DIAD controls. Samples from gantenerumab-treated participants also showed regionally lower amounts of insoluble phosphorylated tau species (pT181, pT205, pT208) and MTBR tau species (354-369, 306-317, 299-317) without apparent differences in insoluble total tau levels. In contrast, brain tissue samples from solanezumab-treated participants did not show significant differences overall in soluble or insoluble levels of Aβ and tau proteoforms in comparison to those from non-treated DIAD individuals. These findings support that amyloid targeting treatment (ATT) with gantenerumab, an antibody that targets fibrillar Aβ, can remove insoluble Aβ from the DIAD brain and also mitigate "downstream" biochemical and pathophysiological changes associated with AD.

KEY SUMMARY: Question: How do amyloid targeting treatments (ATT) affect the Alzheimer disease (AD)-related brain pathologies of soluble and aggregated amyloid-β and tau proteoforms in postmortem tissue?Background: Extracellular amyloid plaques and neurofibrillary tangles (NFTs) are the primary pathological hallmarks of AD. For the past three decades, active and passive immunization against cerebral amyloid-β (Aβ) has constituted one of the primary avenues of disease-modifying intervention in AD. Recently, passive immunizations using anti-Aβ targeting antibodies have demonstrated slowing of cognitive decline in sporadic AD and possibly in dominantly inherited AD (DIAD). In these clinical trials, target engagement has been inferred from Aβ-positron emission tomography (PET) and/or biofluid biomarkers during life. However, to confirm evidence of target engagement more directly, identify which pathological proteoforms are affected, quantify the dose dependent treatment effects of these treatments, and begin to evaluate their putative downstream effects on AD pathophysiology, quantitative biochemical comparisons of amyloid plaques and tau pathology (soluble and insoluble Aβ and tau species) in postmortem brain tissue of treated and untreated AD are needed.Findings: In this study, using high resolution mass spectrometry we measured the soluble and insoluble Aβ and tau proteoforms in the postmortem brain tissue homogenates from DIAN-TU-001 trial participants who were symptomatic and had been treated for ∼ 4 years with gantenerumab (n=4) or solanezumab (n=4), two antibodies that bind to insoluble and soluble Aβ, respectively. Intervals between treatment discontinuation and death ranged from 5 months to 3 years. Comparisons were made with postmortem brain tissue samples from untreated, symptomatic DIAD participants of the DIAN-Obs study (n=40) and from age-relevant, cognitively normal, non-DIAD controls with or without only modest burdens of diffuse Aβ plaques (n=18). Consistent with antemortem Aβ-PET findings in the clinical trial, gantenerumab significantly decreased specific Aβ (Aβ 42 , Aβ 40) proteoforms in the insoluble plaque associated pool (range: 60-80% reduction) compared to the untreated DIAD participants, but without reaching the levels found in the non-DIAD controls. Samples from gantenerumab treated participants also showed significantly lower amount of post-translationally modified Aβ (Aβ 3pGlu) and regionally lower insoluble phosphorylated tau species (pT181, pT205 and pT208), without apparent differences in insoluble total tau levels. In contrast, solanezumab treatment did not show significant effect on the soluble or insoluble levels of Aβ and tau proteoforms in comparison to samples from non-treated DIAD individuals. Significance: These findings support that ATT with gantenerumab, an antibody that targets fibrillar Aβ, can remove insoluble Aβ from the DIAD brain and also mitigate "downstream" biochemical and pathophysiological changes associated with AD.},
}

@article {pmid42856359,
year = {2026},
author = {Petrican, R and Fornito, A},
title = {Alignment with sex-typical brain architecture: Links to mood pathology, sex hormones and transcriptomics of neurodegenerative conditions.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.27.754773},
pmid = {42856359},
issn = {2692-8205},
abstract = {Understanding the mechanisms that underpin the pervasive sex bias in risk for specific psychiatric and neurodegenerative conditions could substantially advance efforts promoting personalized medicine. As a first step towards addressing this issue, we applied imaging transcriptomics and multivariate analysis techniques to data from an adolescent sample enriched in anxiety/depression cases, a child sample enriched in attention deficit hyperactivity disorder (ADHD) cases, and adult patients with treatment resistant major depressive disorder (MDD). We tested whether, across sexes, alignment with female-typical, rather than male-typical, patterns of neural functional connectivity (FC) would relate to a diagnosis (adolescent sample) or severity of symptoms (adult sample) associated with internalizing disorders, which tend to be more often diagnosed in females. To provide preliminary evidence on its functional specificity, we compared the sex-aligned FC profile that distinguished neurotypical adolescents from those diagnosed with depression/anxiety against the sex-aligned FC patterns that distinguished neurotypical children from those diagnosed with ADHD. All the analyses controlled for age within each sample and sex. Finally, we examined the spatial overlap between the sex-aligned FC profile linked to an internalizing diagnosis in adolescence and the transcriptomic maps of genes that show sex-dependent dysregulation in neurodegenerative conditions. Across sexes, increasing alignment with female-typical FC patterns, from sensory-perceptual to default mode regions, discriminated between typically developing and anxious/depressed teens and tracked longitudinal fluctuations in depressive symptoms within adult MDD patients. The identified internalizing-related gradient showed a negative correlation with risk for ADHD in the child sample. The brain regions most strongly aligned with female-, rather than male-, typical FC in depression/anxiety overlapped the spatial expression profiles of genes linked to gonadal hormone synthesis, as well as genes dysregulated in female autism spectrum disorder (ASD) and male neurodegenerative conditions, specifically, Alzheimer's Disease (AD), Huntington's Disease (HD) and Multiple Sclerosis (MS). The brain areas most strongly aligned with male-typical, rather than female-typical, FC patterns overlapped the transcriptomic maps of genes related to androgen and estrogen receptors, as well as of genes dysregulated in male ASD and female neurodegenerative conditions (i.e., AD, HD, MS). Our results raise the possibility that the link between mood pathology and neurodegeneration could reflect a partial, regional reversal of sex-normative functional brain profiles.},
}

@article {pmid42856599,
year = {2026},
author = {Krishingner, T and Fausett, SR},
title = {A New Soaking Protocol to Live Stain C. elegans with Proteostat Dye Reveals Global Patterns of Stress-Induced Protein Aggregation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.30.755777},
pmid = {42856599},
issn = {2692-8205},
abstract = {Protein aggregates are a diverse array of intra- and extracellular structures containing misfolded proteins with limited macromolecular movement. Protein aggregation is induced by aging and cellular stress and is a hallmark of neurodegenerative diseases including Huntington's, Alzheimer's, and Parkinson's. Fluorescent tools to visualize global protein aggregation in whole organisms are, therefore, important for screening genes and compounds that may reduce or alter protein aggregation in connection with improved health outcomes. Fluorescent probes that report low fluidity structures in cells, such as molecular rotor dyes, are gaining popularity and overcome certain limitations of targeted markers such as tagged proteins or antibodies. However, permeability has been a key barrier preventing widespread use of such probes in whole organisms, including in C. elegans . To achieve visualization of non-specific protein aggregates in whole C. elegans nematodes without the need for strain engineering, we have developed a simple soaking protocol. Our protocol overcomes the permeability limitations of the commercially available molecular rotor dye, Proteostat, enabling widespread labeling of protein aggregates in live and post-fixed worms. Here, we present our novel approach and demonstrate quantification of protein aggregates in multiple tissues to detect differences in protein aggregation due to both genotype and treatment effects. We also outline anticipated future applications for this protocol, including its adaptation for other dyes, as well as limitations and special considerations for its use.},
}

@article {pmid42856786,
year = {2026},
author = {Li, X and Qi, H and Zhang, X and Jin, X and Xu, J and Ma, J},
title = {Comparative effects of six exercise modalities on global cognitive function in Alzheimer's disease, Parkinson's disease, and mild cognitive impairment: a systematic review and network meta-analysis.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1877537},
pmid = {42856786},
issn = {1664-2295},
mesh = {Humans ; *Cognitive Dysfunction/therapy/psychology/rehabilitation ; *Parkinson Disease/therapy/psychology/rehabilitation ; *Alzheimer Disease/therapy/psychology/rehabilitation ; *Exercise Therapy/methods ; *Cognition/physiology ; Cognitive Enhancement ; *Exercise ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), Parkinson's disease (PD), and mild cognitive impairment (MCI) are commonly accompanied by cognitive decline. Although exercise is recommended as a non-pharmacological strategy, the comparative effects of different exercise modalities on global cognition remain uncertain.

OBJECTIVE: To compare six exercise modalities-aerobic exercise (AE), mind-body exercise (MBE), resistance training (RT), multi-component exercise (MCE), flexibility training (FT), and functional training (FTr)-for global cognitive function in people with AD, PD, or MCI, and to explore dose-related associations.

METHODS: PubMed, Embase, the Cochrane Library, and Web of Science were searched from inception to January 26, 2026. Randomized controlled trials (RCTs) were synthesized using a frequentist random-effects network meta-analysis (NMA) with standardized mean differences (SMDs) and 95% confidence intervals (CIs). Treatment rankings were summarized using SUCRA. Subgroup analyses, meta-regression, diagnosis-related sensitivity analyses, and CINeMA certainty assessments were also performed.

RESULTS: Twenty-eight trials involving 1,993 participants were included. Compared with control group (CG), AE [SMD = 0.47, 95% CI (0.18, 0.77)], MBE [SMD = 0.79, 95% CI (0.46, 1.11)], RT [SMD = 1.50, 95% CI (0.77, 2.23)], MCE [SMD = 0.83, 95% CI (0.26, 1.40)], and FTr [SMD = 0.83, 95% CI (0.13, 1.53)] improved global cognition, whereas FT showed no clear effect [SMD = -0.20, 95% CI (-1.27,0.87)]. RT ranked first, followed by MCE, FTr, MBE, AE, and FT. Heterogeneity was substantial (τ[2] = 0.23; I[2] = 80%), although no statistically significant global incoherence was detected. RT remained first after the exclusion of AD, PD, or MCI studies. Studies lasting more than 12 weeks, delivered 3-5 times per week, and using sessions of 31-60 min showed favorable pooled effects, but subgroup interaction tests and meta-regression were not significant. Certainty of evidence ranged from low to very low.

CONCLUSION: AE, MBE, RT, MCE, and FTr may improve global cognition in people with AD, PD, or MCI. RT showed the largest effect estimate and the most favorable ranking. However, substantial heterogeneity and sparse evidence for several modalities limit firm conclusions. Exercise selection should be individualized, and dose-related findings require confirmation in adequately powered comparative trials.},
}

Humans
*Cognitive Dysfunction/therapy/psychology/rehabilitation
*Parkinson Disease/therapy/psychology/rehabilitation
*Alzheimer Disease/therapy/psychology/rehabilitation
*Exercise Therapy/methods
*Cognition/physiology
Cognitive Enhancement
*Exercise

@article {pmid42857403,
year = {2026},
author = {Agosta, F and Cecchetti, G and Ghirelli, A and Spinelli, EG and Rugarli, G and Pisano, S and Coraglia, F and Gajate, AMS and Vezzulli, P and Calloni, S and Canu, E and Castelnovo, V and Gilioli, A and Tripodi, C and Freri, F and Bianchi, A and Panzacchi, A and Pepe, G and Falini, A and Chiti, A and Filippi, M},
title = {Residualized occipital amyloid burden and plasma biomarker profiles in relation to ARIA-E during anti-amyloid treatment.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70401},
pmid = {42857403},
issn = {2352-8729},
abstract = {INTRODUCTION: Amyloid-related imaging abnormalities with edema (ARIA-E) represent the main safety concern of anti-amyloid monoclonal antibodies. Whether regional amyloid topology refines ARIA-E risk in real-world practice remains unclear.

METHODS: We analyzed 31 treatment courses in early Alzheimer's disease under European Medicines Agency labeling. Residualized occipital amyloid burden was defined as observed occipital standardized uptake value ratio (SUVR) minus occipital SUVR predicted from global composite SUVR in an expanded baseline positron emission tomography derivation sample (n = 53). Associations with ARIA-E and baseline plasma biomarkers were assessed.

RESULTS: ARIA-E occurred only in the elevated occipital amyloid group: 4/13 treatment courses, versus 0/18 low or comparable courses (Fisher exact p = 0.055). All ARIA-E events involved posterior regions. The elevated pattern showed higher baseline glial fibrillary acidic protein (GFAP), phosphorylated tau (p-tau)181, and p-tau217 levels, whereas amyloid beta 42/40 did not differ between groups. A GFAP + p-tau217 model showed exploratory discrimination of the elevated phenotype (area under the curve: 0.76).

DISCUSSION: Disproportionate occipital amyloid burden may identify a biologically vulnerable subgroup requiring validation in larger cohorts.},
}

@article {pmid42857419,
year = {2026},
author = {Ghirelli, A and Cecchetti, G and Spinelli, EG and Samanes Gajate, AM and Rugarli, G and Pisano, S and Zamboni, IAL and Canu, E and Castelnovo, V and Sibilla, E and Gilioli, A and Tripodi, C and Freri, F and Panzacchi, A and Pepe, G and Chiti, A and Filippi, M and Agosta, F},
title = {Regional amyloid-PET clearance dynamics and anti-Aβ monoclonal antibody therapy: a preliminary real-world study.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70448},
pmid = {42857419},
issn = {2352-8729},
abstract = {INTRODUCTION: Amyloid positron emission tomography (PET) is the reference biomarker for treatment target engagement in anti-amyloid beta (Aβ) therapies in early symptomatic Alzheimer's disease (AD), yet global metrics may mask a regional heterogeneity of amyloid clearance.

METHODS: We report real-world longitudinal amyloid-PET data from 26 patients treated with lecanemab or donanemab for 6 months. Global Centiloids and regional standardized uptake value ratios (SUVRs) were quantified at baseline and 6 months and examined according to treatment, clinical diagnosis, and clinical stage.

RESULTS: Amyloid removal was regionally heterogeneous. Patients with mild cognitive impairment showed greater cortical amyloid reduction than those with mild dementia, while early- and late-onset AD exhibited comparable clearance. Frontal, anterior cingulate, and parietal regions showed the largest SUVR reductions, whereas the occipital cortex and temporal mesial cortex were consistently spared, including in patients reaching global amyloid-PET negativity.

DISCUSSION: Early amyloid clearance following anti-amyloid treatment is regionally heterogeneous and incompletely captured by global PET measures.},
}

@article {pmid42857600,
year = {2026},
author = {Moughamian, AJ and La Vallee, L and Kile, S and Urban, T and Momii, A and Manifield, M and Minton, J},
title = {The Advanced Therapeutics for Alzheimer's Disease Review Board: A multidisciplinary model to facilitate safe access to amyloid-targeting therapies in general neurology across the Sutter Health system.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70479},
pmid = {42857600},
issn = {2352-8729},
abstract = {Amyloid-targeting therapies (ATTs) require workup and monitoring that some general neurologists are uncomfortable with. Sutter Health treats over 3.5 million patients with more than 100 neurologists, but only 5 cognitive specialists. We developed the Advanced Therapeutics for Alzheimer's Disease (ATAD) Review Board, a system-wide model to address the shortage of specialists while enhancing safe access to ATTs across the health system. The ATAD Review Board comprises cognitive specialists, a neuroradiologist, a pharmacist, and a registered nurse program manager. Neurologists submit cases to the board for appropriate patient selection and re-review of cases with side effects. We reviewed 447 cases from 51 neurologists and 77% were eligible for treatment. The annual volume increased 148% in 2025. Total amyloid-related imaging abnormality rate was 17.4% for lecanemab and 28.8% for donanemab. We describe a system-wide review board model that supported ATT prescribing by general neurologists and expanded safe access to ATTs across a large integrated health system.},
}

@article {pmid42857741,
year = {2026},
author = {Shimazu, T and Hoshino, E and Nakaseko, M and Homma, K and Suzuki, S and Horikoshi, K and Maruki, Y},
title = {Caregiver-Reported Behavioral Changes After Donepezil Transdermal Patch Therapy in Alzheimer's Disease: An Exploratory Real-World Network Analysis.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {637015},
pmid = {42857741},
issn = {1176-6328},
abstract = {PURPOSE: To characterize caregiver-reported behavioral changes after donepezil transdermal patch therapy and to examine the descriptive connectivity of co-occurring improvements in patients with Alzheimer's disease (AD).

PATIENTS AND METHODS: This retrospective, single-center observational study included 26 patients meeting the 2011 National Institute on Aging-Alzheimer's Association criteria for probable AD dementia. Approximately 2-4 months after patch initiation, caregivers rated nine behavioral domains using routine, non-validated single-item change assessments as improved, unchanged, or worsened relative to the pre-treatment state. A descriptive co-improvement network was used solely to summarize pairwise co-occurrence of binary improvement indicators using phi-coefficients and observed strength centrality. Because of the small sample and sparse binary events, all network measures were treated as sample-specific descriptive quantities rather than inferential estimates.

RESULTS: The most frequently improved domains were smiling/positive affect (12/26, 46.2%), calmness (9/26, 34.6%), and night-time sleep (8/26, 30.8%). Calmness had the highest observed strength centrality (2.467), followed by grooming behavior (2.059), hobbies/interests (2.009), and housework/instrumental activities of daily living (1.938). Calmness remained the highest-strength node in all 26 leave-one-participant-out sensitivity analyses. No treatment discontinuations or serious adverse events were documented.

CONCLUSION: Caregiver-perceived calmness, assessed as a single non-validated change item, was the most highly connected domain in this small descriptive co-improvement network. The findings are exploratory and do not establish treatment efficacy, a validated agitation-related outcome, temporal direction, or mechanism. Prospective studies using standardized behavioral measures are needed.},
}

@article {pmid42857961,
year = {2026},
author = {Chandrakar, K and Panday, A and Patel, D and Poleboina, S},
title = {Neuroprotective effects of lithium and caffeic acid co-loaded liposomes in diabetes-induced Alzheimer's disease: association with GSK-3β and β-catenin.},
journal = {Nanomedicine (London, England)},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/17435889.2026.2743276},
pmid = {42857961},
issn = {1748-6963},
abstract = {AIM: To investigate the therapeutic effects of co-loaded lithium (Li) and caffeic acid (CA) liposomes in diabetes-induced Alzheimer's disease rats by improving cognitive dysfunction and attenuating neurodegeneration through the modulation of β-catenin/GSK-3β signaling.

METHODS: Li- and CA-co-loaded liposomes were prepared by the ethanol injection method and characterized. A diabetes-induced Alzheimer's disease model was established in male Wistar rats using a high-fat diet followed by low-dose streptozotocin (35 mg/kg) administered intraperitoneally. Li- and CA-co-loaded liposomes were given via the same route every day for 4 weeks. At the end of the experiment, the animals were sacrificed, and various biochemical and oxidative stress parameters, histopathological assessments, and ELISA analyses were performed.

RESULTS: Dual-drug-loaded Li and CA liposomal treatment significantly improved cognitive function, ameliorated metabolic dysfunction, and reduced oxidative stress by restoring antioxidant enzyme levels. Additionally, liposomes attenuated nitrite, acetylcholinesterase, and amyloid-β levels in diabetes-induced Alzheimer's rats. Histopathological assessment confirmed marked neuroprotective and pancreatic protective effects. Further, at a molecular level, Li and CA liposomal treatment reduced the expression of GSK-3β and increased the expression of β-catenin levels in rats.

CONCLUSION: This study provides the first evidence demonstrating the therapeutic potential of Li- and CA-co-loaded liposomes in attenuating diabetes‑associated cognitive dysfunction.},
}

@article {pmid42857983,
year = {2026},
author = {Smitasiri, T and Pongpitakmetha, T and Thanprasertsuk, S and Likitjaroen, Y},
title = {Prevalence and impact of cerebral small vessel lesions in mild cognitive impairment and mild dementia due to Alzheimer's disease patients in memory clinic: Preparation for anti-amyloid therapy in Thailand.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261493065},
doi = {10.1177/13872877261493065},
pmid = {42857983},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) raises global concern with its impact on daily living. Anti-amyloid therapy (AAT) are specific treatments used in mild cognitive impairment (MCI) and mild dementia stage of AD (mild AD). Severe cerebral small vessel disease (SVD) lesions such as microbleeds, superficial siderosis, lacunes, white matter hyperintensities are listed as exclusions criteria for AAT. In Thailand, there is no prevalence study of SVD lesions specifically in these patient groups.ObjectiveThe purpose of this study is to report the prevalence of SVD burdens which are excluded in AAT, in MCI and mild AD patients in Thailand.MethodsThe study was carried out at Memory Clinic in King Chulalongkorn Memorial Hospital. Patients with amnestic MCI and mild AD were diagnosed using clinical criteria, cognitive tests and brain MRI. Visual rating scales were used to evaluate SVD burden based on STRIVE-2 criteria. Baseline characteristics and cognitive tests were retrieved from electronic medical records.ResultsThe study involving 102 patients, 73.5% had MCI, and 26.5% had mild AD. Twenty-one individuals (20.6%) had either more than 4 microbleeds, more than 2 lacunes, or Fazekas score of 3. There was no evidence of superficial siderosis. Individuals without microbleeds had a higher TMSE score (25.4 versus 23.5; p = 0.009).ConclusionsAmong patients with MCI and mild AD, 20.6% met the exclusion criteria for AAT, in part of SVD lesions. These findings provide important information for evaluating the cost-effectiveness of AAT, which become a treatment option for Thai AD patients.},
}

@article {pmid42846808,
year = {2026},
author = {Liu, T and Liu, Y and Zhang, Y and Wang, J and Ren, Y and Fu, S and Han, L and Jiang, P and Chen, J and Li, Y and Luo, H},
title = {Peroxisomes in Alzheimer's disease: emerging mechanistic insights and therapeutic opportunities.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1960320},
pmid = {42846808},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) deposition, tau pathology, synaptic injury, neuroinflammation, oxidative stress, and disrupted organellar homeostasis. Peroxisomes maintain lipid and redox balance through very-long-chain fatty acid (VLCFA) β-oxidation, plasmalogen biosynthesis, and reactive oxygen species (ROS) metabolism. This Review evaluates how peroxisomal alterations may modulate APP processing and Aβ clearance, tau kinase/phosphatase balance, neuroinflammation, oxidative stress, and peroxisome-mitochondria crosstalk. We distinguish human correlational evidence from intervention studies in AD models and mechanistic extrapolation from primary peroxisomal disorders. Current evidence supports a context-dependent vulnerability or amplifier model rather than a universal causal pathway. Peroxisome-targeted interventions remain investigational, and no validated biomarker currently identifies an AD subgroup for such treatment.},
}

@article {pmid42847130,
year = {2026},
author = {Adedayo, BC and Oyeleye, IS and Oyelami, OS and Aro, OP and Ojo, OR and Oboh, G},
title = {Aqueous extracts of Phyllanthus amarus leaf mitigate cognitive impairments by enhancing neurotransmitter regulation and antioxidant defense mechanisms.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/17582024.2026.2744198},
pmid = {42847130},
issn = {1758-2032},
abstract = {AIMS: Phyllanthus amarus (PA, P. amarus), commonly known as stonebreaker, has historically been used in traditional medicine for its medicinal attributes. Cognitive impairment continues to pose a major challenge in neurodegenerative disorders, with natural products being extensively explored as potential therapies. This study examined the effects of aqueous leaf extracts P. amarus on cognitive behaviors and neurochemical markers in scopolamine-induced amnesic rats.

MATERIAL AND METHODS: Rats were administered aqueous PA extracts (50 and 500 mg/kg) or donepezil for a duration of 14 days. Cognitive performance was assessed through behavioral tests followed by neurochemical evaluation of cholinesterases (ChEs), monoamine oxidase (MAO), and purinergic enzymes in the cortex and hippocampus of the rats' brains.

RESULTS: Administration of scopolamine impaired learning and memory and disrupted biochemical homeostasis. Treatment with PA extract significantly improved cognitive performance and attenuated scopolamine-induced alterations in neurotransmitter activity and oxidative stress markers.

CONCLUSION: In conclusion, aqueous leaf extracts of PA treatment may provide a new potential alternative for the treatment and prevention of cognitive impairment and neurochemical changes associated with neurotoxic agents, suggesting its potential to ameliorate scopolamine‑induced cognitive impairment and neurochemical alterations, while further studies are required to establish relevance to Alzheimer's disease pathology.},
}

@article {pmid42847220,
year = {2026},
author = {Cancelloni, V and Caso, V},
title = {Aldosterone, the brain, and the blood pressure ceiling: a neurological case for aldosterone synthase inhibitors in resistant hypertension.},
journal = {American journal of hypertension},
volume = {39},
number = {Supplement_1},
pages = {S57-S65},
doi = {10.1093/ajh/hpag091},
pmid = {42847220},
issn = {1941-7225},
mesh = {Humans ; *Hypertension/drug therapy/physiopathology/enzymology/complications ; *Aldosterone/metabolism ; *Cytochrome P-450 CYP11B2/antagonists & inhibitors/metabolism ; *Blood Pressure/drug effects ; Animals ; *Brain/physiopathology/drug effects/enzymology ; *Antihypertensive Agents/therapeutic use/adverse effects ; Drug Resistance ; Renin-Angiotensin System/drug effects ; *Stroke/prevention & control/physiopathology/etiology ; Treatment Outcome ; Mineralocorticoid Receptor Antagonists/therapeutic use ; Risk Factors ; },
abstract = {Hypertension is the leading modifiable risk factor for stroke and a major contributor to cognitive impairment and dementia, with its global burden increasing alongside population aging. Hypertension promotes cerebrovascular damage through endothelial dysfunction, blood-brain barrier disruption, small vessel disease, and accelerated atherosclerosis, all potentially contributing to both ischemic and hemorrhagic stroke risk. These vascular alterations also contribute to neurodegenerative processes, linking hypertension-particularly when present in midlife-to vascular dementia and Alzheimer's disease. Effective blood pressure control (target <130/80 mm Hg) remains central to primary and secondary stroke prevention and is associated with reduced risks of recurrent stroke and cognitive decline. The renin-angiotensin-aldosterone system plays a central role in hypertension-related cerebrovascular injury, with aldosterone excess contributing to vascular inflammation, oxidative stress, and impaired cerebral autoregulation. Resistant hypertension, often driven by aldosterone dysregulation, is associated with increased cardiovascular and neurological risk. Aldosterone synthase inhibitors such as lorundrostat and baxdrostat represent a novel therapeutic approach targeting aldosterone production. Clinical trials demonstrate significant reductions in systolic blood pressure with favorable safety profiles in patients with uncontrolled or resistant hypertension. Although direct evidence for stroke prevention is currently lacking, indirect data suggest that sustained blood pressure reduction and modulation of aldosterone-mediated vascular damage may lower cerebrovascular risk. Aldosterone synthase inhibitors may be particularly relevant in phenotype-driven, personalized treatment strategies for patients with resistant hypertension or suspected aldosterone excess. However, long-term efficacy, safety, and impact on hard outcomes such as stroke and dementia require confirmation in dedicated trials.},
}

Humans
*Hypertension/drug therapy/physiopathology/enzymology/complications
*Aldosterone/metabolism
*Cytochrome P-450 CYP11B2/antagonists & inhibitors/metabolism
*Blood Pressure/drug effects
Animals
*Brain/physiopathology/drug effects/enzymology
*Antihypertensive Agents/therapeutic use/adverse effects
Drug Resistance
Renin-Angiotensin System/drug effects
*Stroke/prevention & control/physiopathology/etiology
Treatment Outcome
Mineralocorticoid Receptor Antagonists/therapeutic use
Risk Factors

@article {pmid42847291,
year = {2026},
author = {Qiao, Z and Zhao, X and Wang, G and Li, S and Lian, T and Ai, L},
title = {PET-based evaluation of short-term amyloid-β clearance and predictive factors in real-world Alzheimer's disease patients treated with lecanemab.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261493063},
doi = {10.1177/13872877261493063},
pmid = {42847291},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a common progressive neurodegenerative disorder. Lecanemab, an anti-amyloid-β (Aβ) monoclonal antibody, is approved for AD treatment, but real-world efficacy and optimal PET application strategies remain incompletely defined.ObjectiveTo investigate lecanemab's Aβ clearance efficacy, identify predictors of response, and optimize PET application strategies.MethodsA retrospective analysis of Aβ PET-positive AD patients treated with lecanemab for 6-8 months. Paired t-tests evaluated standardized uptake value ratios (SUVR) and cognitive changes; Cohen's Kappa assessed visual-quantitative agreement. Exploratory analyses included partial correlation, regression, and Fisher's exact test.ResultsThirty-eight patients were included. Statistically significant Centiloid (CL) reduction occurred post-treatment (mean difference = 29.39 ± 22.31, p < 0.001), without Mini-Mental State Examination/Montreal Cognitive Assessment or tau PET changes. Twelve patients achieved a CL < 24.1, and 5 were visually negative. Visual-quantitative agreement was fair to poor (positivity Kappa = 0.205; efficacy Kappa = 0.253). Baseline CL, treatment cycles, and SUVRtau were screened by univariate regression (p < 0.05) and entered into a multivariate model (F = 13.693, p < 0.001, adjusted R[2] = 0.507). Baseline CL (standardized-β = 0.594, p < 0.001) and treatment cycles (standardized-β = 0.285, p = 0.022) were independent positive predictors; SUVRtau showed marginal negative association (standardized-β = -0.238, p = 0.052).ConclusionsLecanemab was associated with statistically significant amyloid clearance. Baseline amyloid burden and treatment exposure predicted greater clearance; tau showed attenuating trend. Visual-quantitative discordance supports a hybrid PET pathway: visual screening for inclusivity, serial CL quantification for monitoring, and combined assessment for low-CL patients.},
}

@article {pmid42847294,
year = {2026},
author = {Nakamura, Y and Seiyama, Y and Shimizu, K and Shibasaki, Y and Toda, R and Nakamichi, N and Adachi, J and Hirota, N and Nakai, M and Takahashi, K},
title = {Impact of dementia severity on efficacy of brexpiprazole for agitation in Alzheimer's dementia: A post hoc analysis of a randomized, double-blind, placebo-controlled study in Japan.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261493010},
doi = {10.1177/13872877261493010},
pmid = {42847294},
issn = {1875-8908},
abstract = {BackgroundThe impact of dementia severity on the efficacy of brexpiprazole for agitation associated with Alzheimer's disease in Japanese patients remains unclear.ObjectiveThis post hoc analysis aimed to further examine the efficacy of brexpiprazole with respect to the severity of Alzheimer's dementia (AD), determined using Mini-Mental State Examination (MMSE) score, in a randomized, double-blind, placebo-controlled study conducted in Japanese patients with agitation in AD (AAD).MethodsData from Japanese patients with AAD who received brexpiprazole 1 mg/day or 2 mg/day, or placebo for 10 weeks were analyzed. Changes from baseline in Cohen-Mansfield Agitation Inventory (CMAI) total score were evaluated according to severity of dementia (mild-to-moderate AD: MMSE 11-22; severe AD: MMSE 1-10). Changes from baseline in Clinical Global Impression-Severity of Illness (CGI-S) score were similarly assessed.ResultsAt Week 10, greater improvement was observed primarily with brexpiprazole compared with placebo, whereas efficacy in severe AD was limited with the 1 mg dose. Differences between brexpiprazole and placebo in the mean change from baseline in CMAI total score for mild-to-moderate and severe AD groups were -4.2 (p = 0.0306) and -2.9 (p = 0.2534) for brexpiprazole 1 mg, -7.0 (p = 0.0001) and -7.3 (p = 0.0024) for brexpiprazole 2 mg, respectively. Differences in CGI-S score were -0.3 (p = 0.0598) and -0.4 (p = 0.0762) in brexpiprazole 1 mg, -0.8 (p < 0.0001) and -0.7 (p = 0.0002) in brexpiprazole 2 mg, respectively.ConclusionsBrexpiprazole showed efficacy at the 2 mg dose in Japanese patients, supporting its effectiveness for AAD across AD severities; the effects of the 1 mg dose in severe AD were limited.ClinicalTrials.gov IdentifierNCT03620981 (trial registry name: Brexpiprazole for the Treatment of Patients With Agitation Associated With Dementia of the Alzheimer's Type).Available from https://www.clinicaltrials.gov/study/NCT03620981.},
}

@article {pmid42847732,
year = {2026},
author = {O'shea, DM and Disla, S and Gosling, AE and Valdelamar, GA and Ioana Tolea, M and Galvin, JE},
title = {Limitations of current neuroprotective therapies in dementia with Lewy bodies.},
journal = {Expert review of clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1080/17512433.2026.2742316},
pmid = {42847732},
issn = {1751-2441},
abstract = {INTRODUCTION: Dementia with Lewy bodies (DLB) is characterized by progressive cognitive, neuropsychiatric, motor, autonomic, and sleep impairment. Pharmacological interventions developed with disease-modifying intent have entered clinical testing, but their biological rationale and adequacy of evaluation remain uncertain.

AREAS COVERED: This structured narrative review appraises pharmacological interventions developed with disease-modifying intent in DLB, focusing on biological rationale, central nervous system (CNS) exposure and target engagement, and whether trials adequately tested neuroprotection or altered clinical progression. PubMed/MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched for studies published from January 2023 through 29 July 2026, with trial and registry reconciliation continuing through 30 July 2026. Twelve DLB trials evaluated interventions targeting endosomal signaling, kinase-related proteostasis, autophagy-lysosomal function, cellular bioenergetics, oligomer-associated synaptic injury, or neurotrophic signaling. No completed trial established neuroprotection or disease modification. Interpretation was limited by biological heterogeneity, Alzheimer disease co-pathology, incomplete CNS target-engagement evidence, short treatment duration, small samples, and endpoints unable to distinguish symptomatic effects from altered progression.

EXPERT OPINION: Future trials should prioritize biomarker-supported diagnosis, prospective co-pathology assessment, demonstrated CNS exposure and target engagement, and longer follow-up combining clinical and mechanism-linked outcomes.},
}

@article {pmid42849166,
year = {2026},
author = {Sarwar, S and Mehmood, T and Abbasi, GR},
title = {Region-wise chemometric framework for identifying FTIR functional-group signatures associated with cholinesterase inhibition.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 2},
pages = {109474},
doi = {10.1016/j.compbiolchem.2026.109474},
pmid = {42849166},
issn = {1476-928X},
abstract = {Two key therapeutic targets in the treatment of Alzheimer's disease are acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Understanding the molecular characteristics associated with cholinesterase inhibition is important for the development of new inhibitors. In this study, a chemometric framework integrating Fourier Transform Infrared (FTIR) spectroscopy, Principal Component Analysis (PCA), and region-wise Partial Least Squares Regression (PLSR) was applied to explore spectral-response relationships in newly synthesized flurbiprofen hydrazide and hydrazone derivatives. The dataset comprised 27 compounds with 1868 spectral variables covering the 4000-400 cm[-1] region and experimentally determined AChE and BuChE inhibition activities. Following SNV preprocessing, PCA was used to characterize spectral variability and define five major spectral domains: O-H/N-H, C-H, carbonyl/amide, C-O/C-N, and fingerprint regions. Region-wise PLSR models were evaluated using 5-fold cross-validation based on RMSECV and MAE-CV, with Y-randomization providing an additional assessment of the observed modeling performance. Among the investigated regions, the C-H stretching domain (3000-2800 cm[-1]) showed the most favorable relative cross-validated performance for both AChE (RMSECV = 5.49; MAE-CV = 4.02) and BuChE (RMSECV = 5.09; MAE-CV = 5.13). Y-randomization further supported the response-related performance of the C-H region, particularly for BuChE. Regression coefficient profiles provided additional spectral information for interpreting the response-related variation across the investigated regions. Overall, the FTIR-PCA-PLSR framework provides an interpretable approach for comparative assessment of spectral domains and for generating chemically testable hypotheses regarding cholinesterase inhibition in the investigated flurbiprofen derivative series.},
}

@article {pmid42849557,
year = {2026},
author = {Shrirame, D and Tatode, A and Dabhade, D and Taksande, J and Taksande, B and Kakade, O and Umekar, M},
title = {Intermittent Fasting as a Therapeutic Strategy in Alzheimer's Disease: Understanding of Brain-Derived Neurotrophic Factor Modulation.},
journal = {Physiology & behavior},
volume = {},
number = {},
pages = {115522},
doi = {10.1016/j.physbeh.2026.115522},
pmid = {42849557},
issn = {1873-507X},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease with amyloid-beta (Aβ) plaques, tau tangles, neuroinflammation, and oxidative stress, and it causes cognitive impairment and neuronal loss. The pharmacological treatment is of limited effectiveness, therefore the interest in novel approaches such as intermittent fasting (IF). IF, a nutritional regimen of periodic caloric restriction, has shown a potential to modulate neurodegenerative alterations by metabolic and molecular mechanisms. This review presents the implications of IF in the etiopathogenesis of AD, specifically in controlling brain-derived neurotrophic factor (BDNF). BDNF is a major neurotrophin that plays a key role in synaptic plasticity, neuronal survival, and cognition. Evidence indicates that BDNF is drastically decreased in AD, therefore enhancing disease progression. IF enhances BDNF expression via mechanisms such as improved mitochondrial function, increased ketone body production, and reduced systemic inflammation. Preclinical studies indicate that IF not only upregulates BDNF but also alleviates key AD pathologies, including Aβ deposition and tau hyperphosphorylation. Additionally, clinical data highlight the cognitive benefits of IF and its role in modulating metabolic health, although studies specifically linking IF, BDNF and AD in humans remain limited. This review underscores the need for further research to determine optimal IF protocols and clarify its long-term impact on AD progression. IF's ability to modulate BDNF and other neuroprotective pathways positions it as a promising non-pharmacological intervention for AD management. By bridging metabolic health and neuroprotection, IF offers potential therapeutic synergy for mitigating AD's complex etiopathogenesis.},
}

@article {pmid42850455,
year = {2026},
author = {Padovani, A and Altini, M and Bellelli, G and Bozzali, M and Brignoli, O and Cagnin, A and Cherubini, A and Iannacci, M and Lodi, R and Logroscino, G and Marra, C and Nicora, C and Parretti, S and Sacco, A and Spadin, P and Zappia, M},
title = {Organizing healthcare delivery in the era of disease-modifying therapies for Alzheimer's Disease: an Italian RAND/UCLA consensus.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {11},
pages = {},
pmid = {42850455},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/therapy/diagnosis ; Italy ; *Delivery of Health Care/organization & administration ; Consensus ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) poses a growing clinical and organizational challenge, requiring coordinated, multidisciplinary care models. In Italy, significant regional variability in resources and access to diagnostic services persists, while the implementation of community-based care models, the expanding role of biomarkers, and the advent of disease-modifying therapies (DMTs) further highlight the need for a more coordinated and equitable dementia care network.

OBJECTIVE: Develop system-level recommendations to optimise the organisation of AD care delivery in Italy in anticipation of DMTs introduction.

METHODS: Using the RAND/UCLA Appropriateness Method, a multidisciplinary panel rated 55 statements across nine domains, evaluating appropriateness in two rounds and priority of implementation in a third round.

RESULTS: Consensus was achieved for all statements, with high appropriateness and priority ratings. The statements outline a regional, network-based model organised across territorial services, Spoke and Hub centres, with formal governance responsible for pathway definition and monitoring. Referral pathways from primary care are based on cognitive and frailty assessment, with non-frail patients referred to Spoke for clinical, neuropsychological and neuroradiological evaluation. Patients potentially eligible for DMTs are referred to Hub centres, where diagnostic confirmation is completed and multidisciplinary teams assess treatment eligibility. When authorised, Hub centres are responsible for DMTs prescription and administration. The statements emphasise the need for standardised neuropsychological and neuroradiological protocols for amyloid-related imaging abnormalities (ARIA) monitoring, alongside the progressive adoption of plasma biomarkers, telemedicine, and structured communication with patients and caregivers.

CONCLUSION: This consensus provides a pragmatic framework to support the reorganisation of AD care in Italy, ensuring that every patient is directed to the most appropriate level of care across a flexible regional network.},
}

Humans
*Alzheimer Disease/therapy/diagnosis
Italy
*Delivery of Health Care/organization & administration
Consensus

@article {pmid42851222,
year = {2026},
author = {Sankar, G and R, I and Umasankar, H},
title = {Therapeutic role of deferasirox loaded niosomes against aluminium-maltolate induced Alzheimer disease: A study in Swiss albino mice.},
journal = {The Indian journal of medical research},
volume = {164},
number = {4},
pages = {550-558},
pmid = {42851222},
issn = {0971-5916},
mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/pathology ; *Deferasirox/administration & dosage ; Mice ; Oxidative Stress/drug effects ; Male ; Humans ; Liposomes/chemistry/administration & dosage ; Brain/drug effects/pathology ; Aluminum/toxicity ; Neuroprotective Agents ; Reactive Oxygen Species/metabolism ; Disease Models, Animal ; Organometallic Compounds/toxicity ; Maze Learning/drug effects ; Aluminum Compounds/toxicity ; Pyrones ; },
abstract = {Background and objectives Aluminium, a common component in underarm deodorants, has been reported to increase oxidative stress when present in the bloodstream, and chronic exposure is considered a potential risk factor for Alzheimer disease. This study investigates the neuroprotective and chelating effects of deferasirox (DFX) and its niosome-based formulation (DFX-NS) against aluminium-maltolate (Almal)-induced neurotoxicity in mice. Methods Thirty male Swiss albino mice were randomly assigned into five groups: Control, Almal, Standard (STD), DFX, and DFX-NS. For 21 d, all groups except the control received Almal to induce neurotoxicity, followed by respective treatments for an additional 21 d. After the treatment period, cognitive function was assessed using behavioral tests such as the Morris Water Maze and Y Maze. An in vitro MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was performed on SH-SY5Y cells to evaluate the neuroprotective potential of DFX. In vivo analyses-including elemental analysis (ICP-MS), histopathology, oxidative stress parameters [Reactive Oxygen Species (ROS), Malondialdehyde (MDA), Catalase (CAT)], urine analysis, and protein estimation (Bradford assay)-were performed on the brain, which was isolated after cervical dislocation. Results The results obtained shows that the Deferasirox has optimum capacity to chelate the aluminium ions in the brains of the Alzheimer-diseased swiss albino mice. Though, the evidence obtained were not fully conclusive, but still the results from the niosomes group shows effective treatment option for the Alzheimer disease caused by the aluminium exposure. Interpretation and conclusions The efficacy of DFX and DFX-NS in reducing aluminium-induced neurotoxicity and oxidative stress in the brain proves that DFX could be a possible candidate for treating Alzheimer's patients linked with metal toxicities.},
}

Animals
*Alzheimer Disease/drug therapy/chemically induced/pathology
*Deferasirox/administration & dosage
Mice
Oxidative Stress/drug effects
Male
Humans
Liposomes/chemistry/administration & dosage
Brain/drug effects/pathology
Aluminum/toxicity
Neuroprotective Agents
Reactive Oxygen Species/metabolism
Disease Models, Animal
Organometallic Compounds/toxicity
Maze Learning/drug effects
Aluminum Compounds/toxicity
Pyrones

@article {pmid42851935,
year = {2026},
author = {Ghaderi, S and Pirozzi, MA and Sharbafshaaer, M and Trojsi, F and Mohammadi, S and Fereshtehnejad, SM},
title = {Thalamic quantitative susceptibility mapping and susceptibility source separation: a critical narrative review of evidence and interpretation.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1878540},
pmid = {42851935},
issn = {1664-2295},
mesh = {Humans ; *Thalamus/diagnostic imaging/pathology ; *Magnetic Resonance Imaging/methods ; Animals ; *Brain Mapping/methods ; },
abstract = {Quantitative susceptibility mapping (QSM) measures net tissue magnetic susceptibility, which can conceal coexisting contributions of opposite sign. This is relevant to the thalamus, where nuclei differ in cellular composition, myelinated fibers, and susceptibility contrast. This narrative review evaluates what QSM and magnetic susceptibility source separation, including χ-separation, currently establish about thalamic alterations in aging and neurological disease. The synthesis prioritizes human thalamic evidence and distinguishes it from methodological validation, findings outside the thalamus, and animal experiments. We use paramagnetic component susceptibility (PCS) and diamagnetic component susceptibility (DCS) as the principal notation, with PCS nonnegative and DCS nonpositive. These model-derived components describe magnetic behavior and do not independently identify iron, myelin, calcium, amyloid, or tau. Reduced thalamic bulk susceptibility is repeatedly reported in multiple sclerosis, whereas findings in Alzheimer's disease and Parkinson's disease are less consistent. Differences in acquisition, referencing, segmentation, cohort composition, and treatment of atrophy affect interpretation, although methodological variability does not explain every disagreement. Source separation can provide information concealed by net susceptibility, but depends on relaxation modeling, acquisition conditions, and reconstruction assumptions. Evidence for thalamic protein mapping, calcification of characterization, and treatment monitoring remains limited or indirect. PCS and DCS are research measurements with potential biological interpretability; standardized acquisition and processing, independent tissue validation, longitudinal replication, and clinically useful decision thresholds are required before they can be regarded as validated clinical biomarkers.},
}

Humans
*Thalamus/diagnostic imaging/pathology
*Magnetic Resonance Imaging/methods
Animals
*Brain Mapping/methods

@article {pmid42852183,
year = {2026},
author = {Taylor, JL and Hernandez, B and Lazzeroni, LC and McNerney, MW and Heath, A and Ashford, JW and Cheng, JJ and Chao, S and Bhatt, P and Iv, M and Mojabi, FS and Yesavage, JA},
title = {Parietal and prefrontal transcranial magnetic stimulation (TMS) for mild cognitive impairment (MCI): A pilot randomized clinical trial.},
journal = {Brain disorders (Amsterdam, Netherlands)},
volume = {23},
number = {},
pages = {100322},
pmid = {42852183},
issn = {2666-4593},
support = {IK2 BX004105/BX/BLRD VA/United States ; R01 AG055526/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Even though studies of repetitive transcranial magnetic stimulation (rTMS) have demonstrated improvements in cognitive function, we know little about what site of stimulation would be ideal for improving memory.

METHODS: We investigated two sites: (1) the dorsolateral prefrontal cortex (DLPFC); and (2) the lateral parietal cortex (LPC), a more novel site. Forty amnestic MCI participants were randomized to one of three rTMS groups: (1) active DLPFC; (2) active LPC; and (3) sham. After completing 20 sessions of MRI-neuronavigated, bilateral rTMS, the participants were followed for 6 months. The primary outcome/endpoint was the California Verbal Learning Test-II (CVLT-II) list learning score assessed at 1-week post intervention.

RESULTS: Thirty-seven of 40 randomized participants provided primary endpoint data. Compared with the sham group, the active LPC group performed significantly higher on CVLT-II list learning (p = .048; standardized mean difference (SMD) = 0.86). No significant differences in CVLT-II list learning were detected between the active DLPFC and sham groups (p = .629; SMD = 0.20). Exploratory analyses revealed that the active LPC group performed better than sham on CVLT-II long-delay recall at the 1-week-post primary endpoint (p = .004; SMD = 1.30), and higher on CVLT-II semantic clustering at the 3-month follow-up (p = .015, SMD = 1.16).

CONCLUSION: The parietal cortex is a promising TMS target for improving memory function in MCI. More definitive trials are needed to compare the efficacy of parietal and DLPFC TMS for treatment of memory and cognitive impairment.},
}

@article {pmid42853103,
year = {2026},
author = {Gómez-Oliva, R and Chamorro-Francisco, A and Atienza-Navarro, I and Carrascal, L and Freire-Aragón, MD and Hernández-Galán, R and Nunez-Abades, P and García-Alloza, M and Castro, C},
title = {Sex-Specific Neurogenic and Cognitive Responses in a Murine Model of Accelerated Aging.},
journal = {Aging cell},
volume = {25},
number = {10},
pages = {e70663},
pmid = {42853103},
issn = {1474-9726},
support = {PID2022-142418OB-C21//MICIU/AEI/10.13039/501100011033 ERDF/UE/ ; PID2022-142418OB-C22//MICIU/AEI/10.13039/501100011033 ERDF/UE/ ; FEDER-UCA-2024-A2-13//Andalusia 2021-2027 ERDF/UE Operational Program/ ; },
mesh = {Animals ; Male ; *Neurogenesis/drug effects ; *Aging ; Mice ; *Cognition/drug effects/physiology ; Female ; Disease Models, Animal ; Hippocampus/drug effects ; Sex Characteristics ; },
abstract = {Aging is associated with cognitive deterioration accompanied by a reduction in hippocampal neurogenesis. Murine models have been widely used to study aging and age-related cognitive decline, as they recapitulate many of the key features of the degenerative process. Among these, the SAMP8 strain represents a well-established model of accelerated aging, characterized by early-onset and progressive cognitive impairment, Alzheimer's disease-like neuropathology, and an initial increase in hippocampal neurogenesis that ultimately depletes the neural stem cell pool. Notably, most studies using murine models of aging or neurodegeneration have focused on males or mixed-sex cohorts, leaving sex-specific differences in neurogenesis and cognitive decline largely unexplored. Recent evidence indicates that diterpenoid treatment is associated with improved cognitive performance and enhanced neurogenesis in 6-month-old male SAMP8 mice. However, whether females exhibit similar responses remains unknown. In this study, we characterized sex differences in hippocampal neurogenesis in 6-month-old SAMP8 mice and examined potential sex-dependent effects of diterpenoid therapy. Our findings reveal sex-specific differences in physiological and pathological hippocampal neurogenesis and in responsiveness to ER272 treatment. Male SAMR1 mice displayed higher baseline neurogenesis than females, while male and female SAMP8 mice followed distinct neurogenic aging trajectories. ER272 was associated with improved cognitive performance and preservation of multiple neurogenic parameters in males but showed limited effects in females. These results suggest sex-specific mechanisms of brain aging and indicate that mixed-sex analyses may mask biologically relevant differences, highlighting the importance of considering sex in aging studies and therapeutic development.},
}

Animals
Male
*Neurogenesis/drug effects
*Aging
Mice
*Cognition/drug effects/physiology
Female
Disease Models, Animal
Hippocampus/drug effects
Sex Characteristics

@article {pmid42853296,
year = {2026},
author = {Zhao, J and Bai, Y and Wang, C and Guo, P and Wang, Z and Du, G and Liu, A},
title = {Fraxetin Ameliorates Cognitive Impairment in STZ-Induced Mice: Involvement of Suppressed Microglial Hyperactivation and Improved Mitochondrial Dysfunction.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42853296},
issn = {1557-1904},
support = {2025177//Tianjin Municipal Research Project on Integrated Traditional Chinese and Western Medicine/ ; 2021-I2M-1-028//CAMS Innovation Fund for Medical Sciences/ ; 82574701//National Natural Science Foundation of China/ ; },
mesh = {Animals ; Mice ; *Microglia/drug effects/metabolism ; *Mitochondria/drug effects/metabolism ; *Streptozocin/toxicity ; Male ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism ; *Coumarins/pharmacology/therapeutic use ; Mice, Inbred C57BL ; },
abstract = {Therapeutic for Alzheimer's disease (AD) remains a pressing medical challenge in the field of neuroscience. Natural compounds with structural diversity and multi-target regulatory properties have attracted increasing attention for the treatment of complex neurodegenerative disorders. ‌Fraxetin, previously identified through computer-aided virtual screening, C. elegans assays, and in vitro cellular models as a potential anti-AD natural compound, was further investigated in this study using established in vivo and in vitro systems to evaluate its efficacy in ameliorating cognitive function and elucidate underlying mechanisms. A sporadic AD mouse model was established by intracerebroventricular injection of STZ (3 mg/kg). Fraxetin (3, 10, and 30 mg/kg/day, po.) was administered until the mouse sacrifices. Cognitive performance was evaluated using the novel object recognition, passive avoidance, and Morris water maze tests. STZ induced cerebral energy metabolism disturbances accompanied by mitochondrial dysfunction, neuroinflammation, oxidative stress, neuronal and synaptic loss, and cholinergic system impairment. ‌Behavioral tests confirmed that fraxetin ameliorated cognitive deficits in STZ-induced mice. Further studies revealed that fraxetin preserved mitochondrial structural integrity and enhanced mitochondrial biogenesis, accompanied by upregulation of the Sirt1/PGC-1α/Nrf1/TFAM pathway. In parallel, fraxetin attenuated microglial overactivation and neuroinflammatory responses. Consistently, in LPS-stimulated BV2 microglial cells, fraxetin inhibited nitric oxide and inflammatory mediator release, which was associated with modulation of the TLR2/MYD88/NF-κB signaling pathway, while restoring cellular bioenergetic status, indicating coordinated regulation of inflammation-associated metabolic dysfunction. Importantly, fraxetin attenuated neurodegenerative alterations in STZ-treated mice, as evidenced by reduced neuronal loss and synaptic degeneration. These effects were associated with activation of the BDNF/TrkB/ERK/CREB neurotrophic pathway and inhibition of acetylcholinesterase activity, supporting preservation of synaptic and cholinergic function. This study provides experimental evidence supporting fraxetin as a promising natural multi-target candidate for the intervention of AD.},
}

Animals
Mice
*Microglia/drug effects/metabolism
*Mitochondria/drug effects/metabolism
*Streptozocin/toxicity
Male
*Cognitive Dysfunction/chemically induced/drug therapy/metabolism
*Coumarins/pharmacology/therapeutic use
Mice, Inbred C57BL

@article {pmid42855152,
year = {2026},
author = {Gerson, G and Nogueira, GN and Teixeira, MJ},
title = {Plasma p-tau217 as a biomarker for Alzheimer's disease: diagnostic and prognostic value in clinical and population-based studies.},
journal = {Arquivos de neuro-psiquiatria},
volume = {84},
number = {10},
pages = {1-8},
pmid = {42855152},
issn = {1678-4227},
mesh = {Humans ; *Alzheimer Disease/diagnosis/blood ; Biomarkers/blood ; *tau Proteins/blood ; Prognosis ; Predictive Value of Tests ; Sensitivity and Specificity ; Phosphorylation ; Reproducibility of Results ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia worldwide, and blood-based biomarkers are emerging as accessible diagnostic tools. Plasma phosphorylated tau at position 217 (p-tau217) has shown promise in early detection.

OBJECTIVE: To evaluate the diagnostic accuracy, prognostic value, and applicability of plasma p-tau217 in AD compared with other biomarkers.

METHODS: We conducted an integrative review on the PubMed, Scopus, Embase, and Cochrane Library databases (2018-2024). Eligible observational and diagnostic studies assessing p-tau217 in plasma were included. Study selection and quality assessment followed the Standards for Reporting of Diagnostic Accuracy (STARD) and Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.

RESULTS: We analized 9 studies involving more than 6 thousand participants analyzed. Plasma p-tau217 demonstrated high accuracy (area under the curve [AUC]: 0.86-0.94) for detecting tau and amyloid pathology, outperforming p-tau181. It was effective in diverse populations, asymptomatic individuals, and primary care settings. Longitudinal data suggest predictive value for cognitive decline.

CONCLUSION: Plasma p-tau217 is a reliable and non-invasive biomarker for AD, with applications in diagnosis, prognosis, and treatment monitoring. Standardization and multicenter validation are necessary before clinical implementation.},
}

Humans
*Alzheimer Disease/diagnosis/blood
Biomarkers/blood
*tau Proteins/blood
Prognosis
Predictive Value of Tests
Sensitivity and Specificity
Phosphorylation
Reproducibility of Results

@article {pmid42855813,
year = {2026},
author = {Alten, B and Gokcal, E and Sperling, RA and Shirzadi, Z and Chhatwal, JP and Gurol, ME and Kasner, SE and Greenberg, SM and Cucchiara, BL},
title = {Centrum Semiovale Perivascular Spaces Predict First Hemorrhagic Lesion in Asymptomatic Amyloid-Positive Individuals.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78388},
pmid = {42855813},
issn = {1531-8249},
abstract = {OBJECTIVE: Identification of cerebral amyloid angiopathy (CAA) before its hemorrhagic manifestations remains limited. We aimed to determine whether severe enlarged perivascular spaces in the centrum semiovale (EPVS-CSO) identify a prehemorrhagic stage of sporadic CAA by predicting the first appearance of CAA-related hemorrhagic lesions or incident cognitive decline in amyloid-positive, cognitively unimpaired, hemorrhage-free older adults.

METHODS: We performed a secondary analysis of the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial, a phase 3 randomized study in cognitively unimpaired, amyloid-positive older adults. Participants with baseline hemorrhagic lesions were excluded. Baseline EPVS-CSO severity was dichotomized as severe versus nonsevere. Severe basal ganglia EPVS, more closely associated with hypertensive small vessel disease, was evaluated as a topographical negative-control exposure. The primary outcome was incident strictly lobar cerebral microbleeds or cortical superficial siderosis. The secondary outcome was longitudinal cognitive trajectories measured by the Preclinical Alzheimer Cognitive Composite.

RESULTS: Among 932 participants (mean age 71.7 ± 4.8 years; 61.3% female), 101 (10.8%) had severe EPVS-CSO at baseline. Over a median follow up of 5.1 years (IQR 3.3-5.5 years), 33.7% of those with severe EPVS-CSO developed incident CAA-related hemorrhagic lesions compared with 13.6% of those with nonsevere EPVS-CSO (adjusted HR 2.85, 95% CI 1.91-4.25; p < 0.0001). Severe basal ganglia EPVS was not associated with incident hemorrhagic lesions (adjusted HR 0.87, 95% CI 0.35-2.18; p = 0.77). Severe EPVS-CSO was not associated with early cognitive differences, and participants who developed incident hemorrhagic lesions showed more pronounced cognitive decline.

INTERPRETATION: These findings identify severe EPVS-CSO as a strong predictor of first appearance of CAA-related hemorrhagic lesions in amyloid-positive individuals, supporting integration of amyloid biomarkers into magnetic resonance imaging-based Boston criteria. Identifying markers of the transition of CAA from a nonhemorrhagic to a hemorrhagic stage provides a potential foundation for approaching primary prevention of CAA-related hemorrhage. ANN NEUROL 2026.},
}

@article {pmid42845560,
year = {2026},
author = {Taylor, JP and Alam, JJ and Gomperts, SN and Honig, LS and Prins, ND and Koubiyr, I and Chu, HM and Gardner, A and Blackburn, K and Schoonheim, MM and Teunissen, CE and Galvin, JE},
title = {A Phase 2b randomized clinical trial of the oral p38α inhibitor neflamapimod in dementia with Lewy bodies (DLB).},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10623740/v1},
pmid = {42845560},
issn = {2693-5015},
abstract = {Background: There is high unmet need in dementia with Lewy bodies (DLB). Neflamapimod, showed clinical activity against cognitive and motor endpoints at a dose of 40mg three-times-daily (TID) in a prior phase 2a study in DLB, most prominently in those without Alzheimer disease (AD) co-pathology, assessed by plasma ptau181. Methods: 16-week randomized, placebo-controlled clinical trial, with a 32-week open label extension, conducted at 43 centers in the US, UK and Netherlands. 159 participants with probable DLB by consensus criteria, screened to enrich for patients without AD co-pathology (plasma ptau181≥27.2 pg/mL excluded), randomized between August 2023 and June 2024 to neflamapimod 40mg (80 participants) or matching placebo (79 participants) capsules, TID. Mean age 71.4 (6.1), 85.6% male. Primary outcome measure: change in Clinical Dementia Rating Sum-of-Boxes (CDR-SB). Secondary outcome measures: Timed up and Go test, ADCS Clinical Global Impression of Change, and a study-specific cognitive test battery. Biomarker measures: plasma levels of glial fibrillary acidic protein and neurofilament light chain, and basal forebrain atrophy by structural MRI (sub-study in 18 participants). Results: There was no significant difference between neflamapimod and placebo on the primary outcome measure, change in CDR-SB. There were also no differences seen on secondary clinical outcome measures and the two plasma biomarkers, though in the sub-study, improvement relative to placebo was seen with neflamapimod on change in right basal forebrain volume from baseline to week 16. In exploratory analyses, the treatment group difference in change in CDR-SB favored neflamapimod compared to placebo among participants with low (<21 pg/mL) screening plasma p-tau181. Pharmacokinetic data showed that mean trough neflamapimod plasma drug-concentrations (C trough) were lower than expected, and treatment effect favoring neflamapimod was seen in participants with C trough above the study median. Discontinuation due to adverse events was 2.5% (2 of 79) with neflamapimod and 1.3% (1 of 80) with placebo Discussion: The phase 2a clinical study findings were not replicated, potentially due to the inclusion of a higher proportion of patients with AD co-pathology than targeted and the use of neflamapimod drug product that did not achieve expected plasma drug concentrations. Registered at clinicaltrials.gov on 17 May 2023 (NCT0586966).},
}

@article {pmid42841964,
year = {2026},
author = {Jellinger, KA},
title = {Depression and anxiety in vascular dementia: an update.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {42841964},
issn = {1435-1463},
abstract = {Depression with a prevalence between 20% and 86% and anxiety with a prevalence up to 72% most frequently coexist with vascular dementia (VaD) and reciprocally increase disease risks. Both psychopathological disorders are usually more frequent and more severe in patients with VaD than in those with Alzheimer disease (AD). Although there is a significant association between depression and all-cause dementia, VaD with depression has more comorbidities and higher mortality than without depression. A history of depression prior to dementia is more common than in AD, while its pre-disease state is a matter of discussion. Although the diagnosis of depression related to cerebrovascular disorders is based on the criteria of DSM-V, VaD/depression has been suggested to be a distinct subtype differing from late-life depression and major depressive disorder, whereas others reported broadly similar depressive symptom profiles across VaD, AD, and AD plus VaD. Depression in the course of VaD, which is frequently underdiagnosed and undertreated, has been related to a variety of pathogenic mechanisms, in particular cerebral small vessel disease (CSVD), cerebral white matter lesions, damage to fronto-subcortical brain circuits, neuroinflammation, impaired neurotrophic support, and imbalance of neurotransmitter/kynurenine pathways. Multimarkers, like high CSVD and white matter hyperintensity burden, the presence of visible perivascular spaces, inflammatory markers, neurofilament light chain levels, and other biomarkers may support clinical diagnosis of VaD/depression. Treatment planning should consider a modest response to antidepressants, while treatment of vascular and metabolic comorbidities may provide promising targets for its prevention and treatment. Electroconvulsive therapy and transcranial direct current stimulation as augmentation treatment of an adequate pharmacotherapy are potential strategies in the management of VaD/depression that is known to be often unresponsive to antidepressants only. However, their effectiveness needs further investigation to assess which interventions are appropriate and effective in clinical practice.},
}

@article {pmid42841989,
year = {2026},
author = {Kim, H and Hwang, E and Kim, SJ},
title = {The calcium channel blocker diltiazem ameliorates parthanatos in juvenile neuronal ceroid lipofuscinosis.},
journal = {Journal of molecular medicine (Berlin, Germany)},
volume = {104},
number = {1},
pages = {},
pmid = {42841989},
issn = {1432-1440},
support = {2021R1F1A1049562//Ministry of Education/ ; 2021374C10-2123-BD02//Korea Forestry Promotion Institute/ ; },
mesh = {*Diltiazem/pharmacology/therapeutic use ; *Neuronal Ceroid-Lipofuscinoses/drug therapy/metabolism/pathology/genetics ; Humans ; *Calcium Channel Blockers/pharmacology/therapeutic use ; *Parthanatos/drug effects ; Poly (ADP-Ribose) Polymerase-1/metabolism ; Poly Adenosine Diphosphate Ribose/metabolism ; Calcium/metabolism ; },
abstract = {Accumulation of pre-mutagenic 8-oxoguanine and impaired DNA repair can lead to poly(ADP-ribose) (PAR) accumulation and parthanatos in Alzheimer's disease, the leading cause of age-dependent dementia. However, the occurrence of parthanatos has not been well established in other types of dementia, including juvenile neuronal ceroid lipofuscinosis (JNCL), a major form of juvenile dementia. In this study, we investigated parthanatos-associated pathology in JNCL using patient-derived lymphoblasts (PDLs). Quantitative immunofluorescence microscopy revealed increased accumulation of 8-oxoguanine and PAR in JNCL-PDLs. JNCL is known to exhibit elevated intracellular calcium, which activates PAR polymerase - 1 (PARP1). The L-type calcium channel blocker diltiazem effectively suppressed PAR accumulation in JNCL-PDLs, even under co-treatment with a calcium ionophore. Diltiazem also reduced 8-oxoG accumulation in JNCL-PDLs, although this effect was largely calcium independent. Subcellular fractionation followed by immunoblotting showed that diltiazem enhanced nuclear recruitment of OGG1 and its partner proteins. These protective effects were abolished by OGG1 knockdown, suggesting a dual role of diltiazem in regulating both calcium signaling and OGG1 activity. Collectively, our data identify that parthanatos as novel therapeutic target for JNCL and propose diltiazem as a potential therapeutic agent. KEY MESSAGES: Increased poly(ADP-ribose) accumulation represents a novel therapeutic target in juvenile neuronal ceroid lipofuscinosis caused by CLN3 mutations. Increased PARP1 expression and decreased PARP1 cleavage lead to elevated poly(ADP-ribose) accumulation in juvenile neuronal ceroid lipofuscinosis. Diltiazem ameliorates poly(ADP-ribose) accumulation in patient-derived cell models of juvenile neuronal ceroid lipofuscinosis by suppressing PARP1 expression and 8-oxoguanine accumulation.},
}

*Diltiazem/pharmacology/therapeutic use
*Neuronal Ceroid-Lipofuscinoses/drug therapy/metabolism/pathology/genetics
Humans
*Calcium Channel Blockers/pharmacology/therapeutic use
*Parthanatos/drug effects
Poly (ADP-Ribose) Polymerase-1/metabolism
Poly Adenosine Diphosphate Ribose/metabolism
Calcium/metabolism

@article {pmid42842169,
year = {2026},
author = {Singh, RK and Banerjee, C and Mehan, S},
title = {Beyond Histamine Blockade: Clemastine Fumarate as a Promoter of Myelin Regeneration, Inflammatory Regulation, and Neuroimmune Modulation in CNS Disorders.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42842169},
issn = {1557-1904},
mesh = {Animals ; Humans ; *Clemastine/pharmacology/therapeutic use ; *Central Nervous System Diseases/drug therapy/immunology/metabolism ; *Myelin Sheath/drug effects ; *Neuroimmunomodulation/drug effects/physiology ; *Remyelination/drug effects/physiology ; Neuroinflammatory Diseases/drug therapy/immunology ; *Histamine H1 Antagonists/pharmacology/therapeutic use ; },
abstract = {Clemastine fumarate, a first-generation H1 antihistamine, has emerged as a promising candidate for drug repurposing in neurodegenerative and neuropsychiatric disorders owing to its ability to cross the blood-brain barrier and interact with multiple central nervous system targets. Experimental studies indicate that clemastine promotes remyelination by stimulating the differentiation of oligodendrocyte precursor cells into mature, myelin-producing oligodendrocytes, thereby restoring myelin integrity and improving axonal function in experimental models. In addition to its remyelinating properties, preclinical evidence suggests that clemastine may attenuate neuroinflammation by modulating microglial activation and suppressing pro-inflammatory signalling pathways. These effects have been associated with improved structural and functional outcomes in experimental models of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, stroke, and several neuropsychiatric disorders. Mechanistically, clemastine primarily acts through muscarinic M1 receptor antagonism to promotes remyelination, while additional pathways including PI3K/Akt, ERK1/2, autophagy-related signalling, inflammasome modulation, and sigma-1 receptor signalling have been proposed based on experimental evidence but remain incompletely understood and require further mechanistic validation. Among the neurological disorders investigated multiple sclerosis currently has the strongest clinical evidence with early clinical trials demonstrating modest remyelinating activity. In contrast, evidence supporting the use of clemastine in other neurological disorders remains largely confined to preclinical studies. Several translational challenges also remain unresolved including dose optimisation, treatment timing, long-term safety, sedative and anticholinergic adverse effects, and patient selection. Future research should focus on refining pharmacokinetic properties, optimising dosing strategies, evaluating rational combination therapies, and identifying predictive biomarkers to facilitate clinical translation. Although current evidence highlights the therapeutic potential of clemastine fumarate, its application beyond multiple sclerosis remains investigational and will require rigorous mechanistic studies together with well-designed clinical trials before broader clinical use can be established.},
}

Animals
Humans
*Clemastine/pharmacology/therapeutic use
*Central Nervous System Diseases/drug therapy/immunology/metabolism
*Myelin Sheath/drug effects
*Neuroimmunomodulation/drug effects/physiology
*Remyelination/drug effects/physiology
Neuroinflammatory Diseases/drug therapy/immunology
*Histamine H1 Antagonists/pharmacology/therapeutic use

@article {pmid42842469,
year = {2026},
author = {Mah, E and Gallagher, D and Kang, Y and Gao, F and Ramirez, J and Ismail, Z and Black, SE and Cao, X and Herrmann, N and Marzolini, S and Oh, P and Chen, JJ and Survilla, K and Swardfager, W and Vieira, D and Rapoport, MJ and Lanctôt, KL},
title = {White matter hyperintensities moderate neuropsychiatric response to N-acetylcysteine and exercise therapy in vascular mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261490542},
doi = {10.1177/13872877261490542},
pmid = {42842469},
issn = {1875-8908},
abstract = {BackgroundVascular mild cognitive impairment (vaMCI) is frequently accompanied by neuropsychiatric symptoms (NPS), particularly apathy, which are associated with white matter hyperintensities (WMH). N-acetylcysteine (NAC) combined with exercise may provide neuroprotective benefits.ObjectiveWe hypothesized that baseline frontal and global WMH burden would moderate the neuropsychiatric response to NAC plus exercise. We further hypothesized that the strongest domain-specific effects would be observed for apathy and affective dysregulation.MethodsParticipants with vaMCI were randomized to NAC (2400 mg daily) or placebo plus exercise for 6 months. WMH volumes were quantified using structural MRI. NPS were assessed using the Mild Behavioral Impairment Checklist (MBI-C) at baseline, 3 months, and 6 months. Negative binomial generalized linear mixed models examined WMH × time × treatment interactions. False discovery rate (FDR) correction was applied.ResultsFifty-one participants were included. Lower baseline frontal (β = 0.229, SE = 0.070, FDR-adjusted p = 0.007) and global (β = 0.258, SE = 0.080, FDR-adjusted p = 0.007) WMH volume was associated with greater reductions in NPS over 6 months in the NAC plus exercise group. This effect was driven by improvements in apathy (frontal: β = 0.186, SE = 0.076, FDR-adjusted p = 0.048; global: β = 0.207, SE = 0.089, FDR-adjusted p = 0.049).ConclusionsBaseline WMH burden moderates neuropsychiatric treatment response in vaMCI. These findings support the importance of optimizing care for cerebrovascular risk factors in this vulnerable population.},
}